Abstract To enhance the understanding of molecular mechanisms and mine previously unidentified biomarkers of pediatric atopic dermatitis, PBMC gene expression profiles were generated by RNA sequencing in infants with atopic dermatitis and age-matched controls. A total of 178 significantly differentially expressed genes (DEGs) (115 upregulations and 63 downregulations) were seen, compared with those in healthy controls. The DEGs identified included IL1β, TNF, TREM1, IL18R1, and IL18RAP. DEGs were validated by real-time RT- qPCR in a larger number of samples from PBMCs of infants with atopic dermatitis aged <12 months. Using the DAVID (Database for Annotation, Visualization and Integrated Discovery) database, functional and pathway enrichment analyses of DEGs were performed. Gene ontology enrichment analysis showed that DEGs were associated with immune responses, inflammatory responses, regulation of immune responses, and platelet activation. Pathway analysis indicated that DEGs were enriched in cytokine‒cytokine receptor interaction, immunoregulatory interactions between lymphoid and nonlymphoid cells, hematopoietic cell lineage, phosphoinositide 3-kinase‒protein kinase B signaling pathway, NK cell‒mediated cytotoxicity, and platelet activation. Furthermore, the protein‒protein interaction network was predicted using the STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database and visualized with Cytoscape software. Finally, on the basis of the protein‒protein interaction network, 18 hub genes were selected, and two significant modules were obtained. In conclusion, this study sheds light on the molecular mechanisms of pediatric atopic dermatitis and may provide diagnostic biomarkers and therapeutic targets. Abbreviations: AD, atopic dermatitis; BP, biological process; CC, cellular component; DEG, differentially expressed gene; GO, gene ontology; MF, molecular function; PIP, protein‒protein interaction; RNA-seq, RNA sequencing Introduction Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in early childhood. It affects children with a prevalence of up to 20% and adults with prevalence rates of 7‒10% ([27]Weidinger et al., 2018). AD is a complex multifactorial disease, thought to result from an interplay between environmental factors, an impaired skin barrier, and immune dysfunctions; however, the overall pathologic mechanisms are still not fully understood ([28]Langan et al., 2020). Although much has been learned about the molecular basis of AD, most investigations have focused on adult AD with years of disease activity that is remarkably different from those of early-onset AD in children. Few studies have profiled skin tissue in infants with AD ([29]Brunner et al., 2019, [30]2018; [31]Cole et al., 2014; [32]Esaki et al., 2016). Over the last decade, RNA sequencing (RNA-seq)-based transcriptome profiles have been implemented in identifying transcripts and pathways in many diseases; however, limited studies using this method were performed on skin tissues in AD, particular in children with AD ([33]Brunner et al., 2019; [34]Cole et al., 2014). Only one study conducted has compared transcriptome profiles of both blood and skin tissue in children with AD at various ages up to age 5 years ([35]Brunner et al., 2019). Given that AD is an early childhood disease that generates a systemic immunological response and that 60% of all cases of AD begin during the first year of life ([36]Bieber, 2008), we aimed to discover signature biomarkers of AD in infants that might help to identify new diagnostic biomarkers and molecular targets for treatment modalities in pediatric AD. For this purpose, we performed an integrative study comprising RNA-seq transcriptome profile of peripheral blood cells obtained from infants with AD or healthy infants, quantitative RT-PCR, and systems biology analysis. Results Analysis of gene expression by RNA-seq A total of 100 infants with moderate or severe AD in the first year of life and 20 age-matched healthy control infants were initially recruited ([37]McAleer et al., 2019). PBMCs were isolated from 42 patients and 19 controls. RNA samples were extracted, and only 27 samples from patients with AD and 17 controls passed quality control and were used in this study. The use of samples is presented in a schematic flow chart ([38]Figure 1). We performed RNA-seq profiles on PBMCs from randomly selected infants with AD (n = 8) and controls (n = 5) using the Illumina platform. Differential expression analysis was conducted to identify differentially expressed genes (DEGs) between AD and controls on the basis of the following criteria: false discovery rate <0.05 and fold change ≥1.5. We identified a total of 178 significantly DEGs with 115 upregulations and 63 downregulations in AD PBMCs when compared with those in control PBMCs. Among highly upregulated genes, we identified IL1β, previously shown to be upregulated in the serum of adult patients with AD ([39]Thijs et al., 2018); TNF, a proinflammatory cytokine whose role in the pathogenesis of AD is well-known ([40]Jacobi et al., 2005; [41]Sumimoto et al., 1992); and early growth response genes EGR2 and EGR3, known to have a crucial role in the regulation of the immune system ([42]Li et al., 2012). Other upregulated genes included TREM1, previously shown to be elevated in lesional skin and serum in patients with AD ([43]Suarez-Farinas et al., 2015), and CXCL5, an inflammatory chemokine found to be at elevated levels in the blood of patients with AD ([44]Brunner et al., 2017). Among downregulated genes, we identified IL18R1 and IL18RAP found to be associated with AD ([45]Hirota et al., 2012). We summarized the 10 DEGs randomly selected from our study and compared their expression with published data ([46]Table 1). A complete list of DEGs in blood cells is shown in [47]Table 2. Figure 1. [48]Figure 1 [49]Open in a new tab The overall framework of study design. AD, atopic dermatitis; QC, quality control. Table 1. A List of 10 Differentially Expressed Genes Randomly Selected from Our Study and Their Changes Identified in Older Children and Adults with AD on the Basis of the Literature DEG Children Aged 0‒1 y Tissue, Down/Up Older Children Tissue, Down/Up Adults Tissue, Down/Up IL18RAP This study PBMCs; Down [50]Brunner et al. (2019) 4 mo, 5 y AD LS versus HC skin; Up [51]Ewald et al. (2015) and [52]Hirota et al. (2012) Susceptibility loci for AD; AD LS versus NS, Up IL18R1 This study PBMCs; Down NA Hirota et al. (2012) Susceptibility loci for AD IL1β This study PBMCs; Up [53]Cole et al. (2014) 6‒16 years AD NS versus HC skin; Down [54]McAleer et al. (2019) and [55]Thijs et al. (2018) AD versus HC Serum, Up; AD versus HC SC, Down TNF This study PBMCs; Up [56]Brunner et al. (2019) [57]Sumimoto et al. (1992) 1‒15 y AD LS versus HC skin, Up; AD NS versus HC skin, Up; AD versus HC Plasma, Up [58]Suarez-Farinas et al. (2015) and [59]Thijs et al. (2018) AD LS versus NS, Up AD versus HC Serum, Up TREM1 This study PBMCs; Up NA [60]Suarez-Farinas et al. (2015) and [61]Thijs et al. (2018) AD versus HC Serum, Up AD LS versus NS, Up EGR3 This study PBMCs; Up NA [62]Suarez-Farinas et al. (2011) AD LS versus HC skin, Down; AD NS versus HC skin, Down EGR2 This study PBMCs; Up [63]Brunner et al. (2019) 4 mo, 5 y AD LS versus HC skin, Down; AD NS versus HC skin, Down Hirota et al. (2012) Susceptibility loci for AD EGR1 This study PBMCs; Up [64]Brunner et al. (2019) 4 mo, 5 y [65]Cole et al. (2014) 6‒16 y AD LS versus HC skin, Down; AD NS versus HC skin, Down; AD NS versus HC skin; Up [66]Suarez-Farinas et al. (2011) AD LS versus HC skin, Up; AD NS versus HC skin, Up NLRP3 This study PBMCs; Up [67]Brunner et al. (2019) AD LS versus HC skin, Down; AD NS versus HC skin, Down [68]Niebuhr et al. (2014) AD LS versus HC skin, Down FOSL1 This study PBMCs; Up [69]Brunner et al. (2019) 6‒16 y [70]Cole et al. (2014) 6‒16 y AD LS versus HC skin, Up AD NS versus HC skin; Up [71]Ewald et al. (2015) and [72]Suarez-Farinas et al. (2011) AD LS versus HC skin, Up; AD LS versus AD NL skin, Up; AD LS versus NS, Up [73]Open in a new tab Abbreviations: AD, atopic dermatitis; DEG, differentially expressed gene; Down, downregulated; HC, healthy control; LS, lesional skin; NA, nonavailable; NS, nonlesional skin; SC, stratum corneum; Up, upregulated. Table 2. Differentially Expressed Genes in PBMCs from Infants with AD Gene Log[2]FC FC P-Value FDR GLDC ‒2.265 0.208 3.34E−11 5.29E−07 HRASLS2 ‒2.086 0.236 2.18E−05 0.00576 SDC1 ‒1.809 0.285 0.00044 0.03940 CDC20 ‒1.749 0.297 6.14E−05 0.01085 IL18RAP ‒1.702 0.307 1.56E−07 0.00031 INTU ‒1.664 0.316 2.70E−05 0.00658 IGKV3-11 ‒1.655 0.317 0.00031 0.03247 KIR2DL3 ‒1.524 0.348 6.36E−05 0.01095 [74]AL645929.1 ‒1.497 0.354 4.41E−05 0.00906 IGKV5-2 ‒1.487 0.357 1.46E−07 0.00031 PLEKHG7 ‒1.472 0.360 1.29E−05 0.00474 BHLHA15 ‒1.437 0.369 0.00021 0.02593 IGHV3-21 ‒1.412 0.376 0.00038 0.03721 GTSE1 ‒1.402 0.378 1.17E−05 0.00465 [75]AC007278.2 ‒1.389 0.382 0.00032 0.03341 FASLG ‒1.367 0.388 7.97E−05 0.01202 MCM10 ‒1.357 0.390 4.54E−05 0.00923 NCAPG ‒1.350 0.392 1.58E−05 0.00534 IGJ ‒1.349 0.393 0.00015 0.02018 SPC24 ‒1.328 0.398 2.10E−06 0.00210 UBE2C ‒1.326 0.399 0.00038 0.03721 [76]AL365475.1 ‒1.321 0.400 7.85E−05 0.01196 CCDC150 ‒1.276 0.413 0.00016 0.02125 KLRD1 ‒1.257 0.418 7.68E−05 0.01192 MELK ‒1.255 0.419 0.00010 0.01551 SKA3 ‒1.252 0.420 0.00013 0.01832 [77]AC007278.1 ‒1.226 0.428 0.00063 0.04921 IGLV1-44 ‒1.225 0.428 3.86E−05 0.00849 NCR1 ‒1.207 0.433 0.00056 0.04636 IGLV3-19 ‒1.192 0.438 2.91E−05 0.00687 KLRC4 ‒1.176 0.443 0.00020 0.02444 RNF165 ‒1.134 0.456 0.00046 0.04029 IGLV8-61 ‒1.111 0.463 7.35E−05 0.01176 MYBL1 ‒1.104 0.465 2.63E−08 0.00011 [78]AC006480.2 ‒1.093 0.469 0.00013 0.01832 AURKB ‒1.073 0.475 0.00026 0.02917 SLCO4A1 ‒1.057 0.481 7.15E−05 0.01167 IGLV2-8 ‒1.057 0.481 0.00022 0.02608 IGLV2-23 ‒1.037 0.487 2.85E−05 0.00684 IL18R1 ‒1.030 0.490 5.41E−08 0.00014 IGLC2 ‒1.022 0.493 0.00019 0.02387 [79]AL683813.1 ‒1.020 0.493 0.00058 0.04670 [80]AC010536.1 ‒1.013 0.496 0.00056 0.04625 STRIP2 ‒1.002 0.499 0.00030 0.03156 KLRF1 ‒0.993 0.502 0.00023 0.02686 XYLB ‒0.971 0.510 0.00039 0.03721 SH2D2A ‒0.964 0.513 0.00018 0.02284 IGKV1-5 ‒0.958 0.515 1.51E−05 0.00519 IGKV4-1 ‒0.958 0.515 0.00011 0.01580 IGLV2-11 ‒0.947 0.519 4.07E−05 0.00859 PIWIL2 ‒0.931 0.525 0.00042 0.03910 SLFN13 ‒0.890 0.540 8.03E−06 0.00340 IGKV1-12 ‒0.870 0.547 0.00055 0.04604 PDGFD ‒0.834 0.561 0.00018 0.02275 ABCB9 ‒0.821 0.566 0.00043 0.03940 ISG20 ‒0.796 0.576 0.00025 0.02887 KIF2C ‒0.782 0.582 0.00037 0.03676 IGKV3-15 ‒0.777 0.584 0.00057 0.04636 TTC22 ‒0.762 0.590 0.00044 0.03940 C5orf56 ‒0.705 0.613 2.15E−05 0.00576 DLG3 ‒0.696 0.617 0.00054 0.04512 COLQ ‒0.609 0.656 3.98E−05 0.00859 SPATS2 ‒0.608 0.656 5.20E−05 0.00992 APP 0.598 1.514 4.61E−08 0.00014 MCL1 0.661 1.581 4.80E−06 0.00256 MAML3 0.661 1.581 1.85E−05 0.00576 KCNQ1 0.732 1.661 0.00040 0.03721 RFX2 0.754 1.687 7.45E−05 0.01180 PGRMC1 0.779 1.716 6.33E−05 0.01095 PRXL2C 0.786 1.724 0.00061 0.04852 FRMD4B 0.842 1.793 0.00036 0.03648 ANXA1 0.869 1.827 5.64E−05 0.01051 ESAM 0.912 1.881 0.00049 0.04315 HIST1H2AC 0.916 1.887 0.00045 0.04004 RAPH1 0.923 1.896 0.00028 0.03031 ADAM9 0.940 1.918 0.00027 0.03031 TUBA1A 1.021 2.029 0.00060 0.04766 LDLR 1.068 2.097 1.29E−05 0.00474 CPNE2 1.098 2.140 3.93E−06 0.00244 ZNF185 1.183 2.270 0.00055 0.04604 MYADM 1.187 2.278 6.10E−05 0.01085 F5 1.301 2.464 2.45E−06 0.00210 AHR 1.343 2.536 0.00058 0.04670 LMNA 1.382 2.606 7.10E−05 0.01167 HIST2H2BE 1.467 2.765 4.13E−06 0.00244 GNG11 1.491 2.810 0.00023 0.02700 HIST1H2BJ 1.560 2.948 0.00033 0.03358 FAM129B 1.570 2.968 0.00034 0.03455 SH3BGRL2 1.617 3.067 0.00028 0.03031 PADI4 1.625 3.085 0.00040 0.03721 LTBP1 1.635 3.106 0.00057 0.04636 ICAM1 1.645 3.128 0.00057 0.04636 FAM20C 1.662 3.165 0.00049 0.04315 C2orf88 1.675 3.194 2.45E−05 0.00625 NAMPT 1.701 3.252 0.00029 0.03156 CD14 1.703 3.256 0.00042 0.03898 SCN1B 1.728 3.312 5.16E−05 0.00992 NRGN 1.740 3.340 1.77E−05 0.00560 LGALS12 1.748 3.359 0.00011 0.01596 GGTA1P 1.751 3.367 0.00026 0.02917 PPP1R15A 1.762 3.392 0.00038 0.03721 SEPT5 1.765 3.399 3.99E−06 0.00244 TAL1 1.767 3.402 2.23E−06 0.00210 PDGFC 1.769 3.408 6.82E−05 0.01149 PRKAR2B 1.781 3.436 1.96E−06 0.00210 RAB20 1.807 3.499 0.00039 0.03721 PLAUR 1.810 3.505 0.00051 0.04372 CTTN 1.813 3.513 1.97E−05 0.00576 GP6 1.813 3.515 1.72E−-05 0.00557 GAS2L1 1.834 3.565 0.00016 0.02125 CLDN5 1.864 3.641 0.00018 0.02321 PEAR1 1.867 3.649 1.71E−05 0.00557 KLF4 1.871 3.657 0.00039 0.03721 SOWAHC 1.872 3.661 0.00051 0.04372 TSPAN9 1.879 3.679 4.20E−06 0.00244 MMP25 1.903 3.740 7.48E−06 0.00329 LGALSL 1.942 3.843 4.86E−06 0.00256 ANPEP 1.943 3.846 7.25E−05 0.01171 SPARC 1.954 3.875 0.00028 0.03031 FAXDC2 1.966 3.907 2.52E−06 0.00210 ATP2B1-AS1 1.969 3.914 0.00014 0.01999 ITGA2B 1.979 3.942 0.00015 0.02018 NLRP3 1.995 3.987 4.40E−05 0.00906 ITGB3 1.999 3.998 0.00016 0.02125 ITGB5 2.001 4.004 5.57E−05 0.01051 BEND2 2.012 4.034 0.00051 0.04372 TRIB1 2.015 4.042 0.00030 0.03156 PTX3 2.039 4.109 0.00024 0.02744 VWF 2.054 4.152 1.32E−05 0.00474 DUSP6 2.066 4.186 0.00014 0.01973 ELOVL7 2.109 4.314 2.10E−05 0.00576 ALOX12 2.134 4.389 2.96E−05 0.00690 HOMER3 2.140 4.406 3.76E−05 0.00839 ADM 2.142 4.414 0.00045 0.04004 PDE5A 2.151 4.442 0.00022 0.02608 TMEM40 2.166 4.489 0.00039 0.03721 MPIG6B 2.178 4.526 1.16E−06 0.00147 ENKUR 2.178 4.527 0.00062 0.04886 LRP3 2.194 4.575 5.93E−05 0.01085 [81]AC245128.3 2.195 4.579 2.51E−05 0.00630 TUBB1 2.212 4.633 1.31E−05 0.00474 TREML1 2.258 4.785 3.55E−06 0.00244 CAVIN2 2.277 4.847 5.78E−06 0.00269 IER3 2.290 4.891 6.17E−05 0.01085 WLS 2.302 4.930 2.16E−05 0.00576 NRIP3 2.330 5.030 0.00021 0.02593 EMP1 2.340 5.062 1.21E−06 0.00147 GP1BA 2.342 5.069 5.15E−06 0.00256 PF4 2.349 5.095 2.92E−06 0.00231 TNF 2.352 5.107 2.47E−06 0.00210 PPBP 2.379 5.204 9.63E−07 0.00139 SGK1 2.443 5.439 5.32E−06 0.00256 CLU 2.464 5.517 0.00052 0.04420 TREM1 2.464 5.519 9.14E−07 0.00139 FCAR 2.472 5.549 1.91E−05 0.00576 LUCAT1 2.560 5.898 0.00050 0.04362 GP9 2.577 5.968 4.27E−06 0.00244 CMTM5 2.580 5.981 2.02E−05 0.00576 [82]AL391903.1 2.604 6.079 4.05E−05 0.00859 ABLIM3 2.620 6.146 2.44E−05 0.00625 CALD1 2.629 6.185 2.17E−05 0.00576 B3GNT5 2.681 6.415 6.12E−06 0.00277 [83]AC007032.1 2.695 6.474 0.00062 0.04876 SPOCD1 2.713 6.556 5.34E−06 0.00256 ZNF503 2.843 7.177 8.15E−06 0.00340 CXCL5 2.848 7.202 0.00016 0.02125 SEC14L5 2.856 7.241 3.18E−05 0.00730 AQP10 2.879 7.356 0.00044 0.03940 PDZK1IP1 3.014 8.080 0.00043 0.03921 IL1B 3.127 8.736 7.60E−05 0.01192 SPX 3.184 9.090 3.38E−06 0.00244 HRAT92 3.192 9.140 1.82E−09 1.44E-05 CLEC1B 3.356 10.238 8.70E−07 0.00139 ID1 3.458 10.986 3.66E−05 0.00827 EGR3 3.496 11.279 0.00030 0.03156 EGR1 3.517 11.447 0.00033 0.03344 FOSL1 3.557 11.767 1.48E−05 0.00519 EGR2 3.763 13.572 0.00024 0.02800 [84]Open in a new tab Shown is a list of genes differentially expressed in the blood of children with AD children versus in age-matched healthy control, meeting criteria of FC ≥1.5 and FDR <0.05. Abbreviations: AD, atopic dermatitis; FC, fold change; FDR, false discovery rate; MMP, matrix metalloproteinase; VWF, Von Willebrand factor. Validation of RNA-seq data by RT-qPCR To confirm the results of RNA-seq, real-time RT-qPCR was performed to detect the mRNA expression of five randomly selected DEGs in PBMCs from controls (n = 17) and infants with AD (n = 27). As shown in [85]Figure 2a-e, the mRNA levels of all five genes—IL18RAP, IL1β, TNF, TREM1, and EGR3—had significant differences between the AD and control groups in accordance with RNA-seq results. Figure 2. [86]Figure 2 [87]Open in a new tab Validation of RNA-sequencing data by RT-qPCR. RT-qPCR analyses for five genes from the top 10 differentially expressed genes identified by high-throughput RNA sequencing: (a) IL18RAP, (b) IL1β, (c) TNF, (d) TREM1, and (e) EGR3 in children with AD (n = 27) and healthy controls (n = 17). Fold change was calculated by 2-ΔΔCT method. The normalized expression data were log[2] transformed and shown as the means ± SD. Significant difference among groups was calculated by unpaired t test with Welch’s correction for normal distribution or with Mann‒Whitney rank-sum test for non-normal distribution data. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001 Effect of infant’s age on gene expression in the blood of infants with AD We wondered whether the infant’s age has an effect on gene expression in the blood of patients with AD in the first year of life. Previous studies have shown that differences in skin microbiome depend on infant’s age in healthy infants ([88]Capone et al., 2011) and AD infants ([89]Nakamura et al., 2020). To elucidate the effect of age, we stratified patients with AD and healthy controls accordingly (0‒6 months and 7‒12 months) and performed differential expression analysis on RNA-seq data. [90]Table 3 summarizes the DEGs between four groups: patients with AD aged >6 months (n = 5) versus age-matched healthy controls (n = 2), patients with AD aged <6 months (n = 3) versus age-matched healthy controls (n = 3), patients with AD aged >6 months versus patients with AD aged <6 months, and healthy controls aged >6 months versus healthy controls aged <6 months. Interestingly, four DEGs that have been identified between AD infants and healthy controls and validated by RT-qPCR in this study (IL1B, TNF, TREM1, and EGR3) were differentially expressed in patients with AD aged <6 months compared with those in age-matched healthy controls, suggesting its unique differential expression in the first 6 months of life in patients with AD. IL18RAP has been shown to be differentially expressed in both age groups between patients with AD and healthy controls, suggesting no effect of age stratification on this DEG in patients with AD ([91]Table 4). Data were further validated by RT-qPCR ([92]Figure 3a-e). Four DEGs (IL1B, TNF, TREM1, and IL18RAP) showed significant differential expression affected by age in accordance with RNA-seq results. Expression of EGR3 showed a trend to be affected by age; however, it was not significant as shown by RNA-seq analysis. Altogether, these data indicate that identified DEGs in patients with AD in the first year of life could be affected by age; however, more samples are required to approve this effect. Table 3. Effect of Infant’s Age on Gene Expression in Infants with AD and HCs Gene Log2FC FC P-Value FDR AD aged >6 mo (n = 5) versus HCs (n = 2) MTCO3P12 ‒8.823 0.002 5.674E-09 9.209E-05 IGKV1-16 ‒3.584 0.083 4.496E-06 6.483E-03 GLDC ‒2.244 0.211 1.331E-06 3.086E-03 IL18RAP ‒1.968 0.256 1.241E-06 3.086E-03 MIF-AS1 ‒1.916 0.265 1.954E-05 1.885E-02 WASHC1 ‒1.739 0.300 1.974E-05 1.885E-02 SNHG22 ‒1.500 0.354 7.604E-05 4.255E-02 ENSG00000273295 ‒1.294 0.408 5.821E-07 2.362E-03 ENSG00000260404 ‒1.045 0.485 4.011E-06 6.483E-03 KLRF1 ‒1.011 0.496 2.685E-05 2.294E-02 ITGB1 0.883 1.844 8.051E-05 4.355E-02 H2AC6 1.538 2.904 9.485E-05 4.966E-02 PRKAR2B 2.157 4.460 5.766E-05 3.743E-02 GNG11 2.278 4.849 3.485E-05 2.507E-02 PEAR1 2.424 5.366 6.523E-05 4.072E-02 MPIG6B 2.499 5.651 1.643E-05 1.885E-02 PF4 2.520 5.738 7.597E-05 4.255E-02 FAXDC2 2.540 5.816 5.347E-05 3.616E-02 CAVIN2 2.585 6.000 8.349E-06 1.042E-02 PPBP 2.589 6.018 3.512E-06 6.483E-03 ITGB3 2.595 6.043 3.553E-05 2.507E-02 TUBB1 2.612 6.112 3.955E-06 6.483E-03 TREML1 2.710 6.542 2.979E-05 2.417E-02 FPR1 3.011 8.060 2.393E-05 2.158E-02 CLEC4F 3.292 9.798 1.938E-07 1.048E-03 ABLIM3 3.372 10.355 3.510E-05 2.507E-02 FPR2 3.438 10.836 7.061E-05 4.244E-02 LIN7A 4.010 16.113 4.794E-06 6.483E-03 SEC14L5 4.348 20.367 8.718E-07 2.830E-03 DDX11L10 6.851 115.408 1.897E-05 1.885E-02 IGHV5-10-1 9.633 793.981 2.177E-08 1.767E-04 AD aged <6 mo (n = 3) versus HCs (n = 3) ENSG00000271993 ‒6.451 0.011 1.429E-04 6.675E-03 LOC107987373 ‒6.102 0.015 9.330E-04 2.534E-02 ENSG00000254851 ‒4.136 0.057 7.154E-04 2.125E-02 ENSG00000266302 ‒4.021 0.062 3.886E-04 1.392E-02 GPR82 ‒3.736 0.075 3.149E-04 1.211E-02 ENSG00000244167 ‒3.326 0.100 1.761E-05 1.365E-03 GAPDHP1 ‒3.207 0.108 7.216E-04 2.133E-02 CHL1 ‒3.046 0.121 7.483E-04 2.173E-02 SDC1 ‒2.950 0.129 5.232E-04 1.712E-02 RAVER2 ‒2.943 0.130 4.456E-05 2.817E-03 FCGR3B ‒2.920 0.132 6.584E-05 3.805E-03 SLC4A10 ‒2.904 0.134 2.548E-06 2.678E-04 ZBED2 ‒2.888 0.135 2.211E-03 4.666E-02 SSPN ‒2.633 0.161 4.028E-04 1.426E-02 LOC730101 ‒2.581 0.167 2.129E-03 4.537E-02 GLDC ‒2.464 0.181 2.327E-05 1.709E-03 IGLV2-18 ‒2.420 0.187 3.579E-05 2.360E-03 IGHV3-13 ‒2.394 0.190 5.888E-04 1.865E-02 IGHV3-21 ‒2.390 0.191 1.176E-12 7.064E-10 CHAC2 ‒2.389 0.191 2.231E-05 1.660E-03 IGKV3D-20 ‒2.308 0.202 3.317E-04 1.251E-02 TNFRSF17 ‒2.299 0.203 1.029E-06 1.254E-04 CDC20 ‒2.240 0.212 4.534E-09 1.230E-06 IGHV3-15 ‒2.202 0.217 3.022E-08 5.775E-06 MIR3142HG ‒2.184 0.220 8.995E-05 4.727E-03 LINC01355 ‒2.181 0.220 3.300E-04 1.249E-02 ENSG00000230521 ‒2.172 0.222 1.578E-04 7.192E-03 BHLHE41 ‒2.121 0.230 1.844E-03 4.116E-02 BHLHA15 ‒2.112 0.231 8.746E-04 2.427E-02 PPP1R17 ‒2.103 0.233 2.441E-04 1.004E-02 OR2A9P ‒2.084 0.236 2.116E-03 4.522E-02 ENSG00000275481 ‒2.066 0.239 1.494E-04 6.923E-03 PARS2 ‒2.045 0.242 2.013E-03 4.369E-02 EOMES ‒2.011 0.248 1.357E-04 6.399E-03 IGHGP ‒1.983 0.253 8.716E-04 2.426E-02 JCHAIN ‒1.982 0.253 1.711E-06 1.918E-04 IGHV3-72 ‒1.981 0.253 7.772E-05 4.244E-03 CISH ‒1.930 0.262 7.131E-08 1.187E-05 CD180 ‒1.920 0.264 1.204E-03 3.039E-02 MCM10 ‒1.919 0.264 6.847E-05 3.890E-03 LINC02273 ‒1.918 0.265 1.005E-04 5.058E-03 KLRC4 ‒1.911 0.266 8.811E-08 1.398E-05 IGKV1-6 ‒1.891 0.270 7.272E-04 2.138E-02 TRGV8 ‒1.860 0.276 1.861E-03 4.134E-02 IGLV3-19 ‒1.857 0.276 8.468E-08 1.356E-05 SLC23A3 ‒1.846 0.278 1.713E-03 3.930E-02 C1orf220 ‒1.844 0.279 8.631E-04 2.407E-02 IGKV1-17 ‒1.841 0.279 9.117E-07 1.136E-04 IGHG1 ‒1.835 0.280 9.853E-04 2.625E-02 ENSG00000258810 ‒1.826 0.282 1.423E-03 3.409E-02 TRGV10 ‒1.785 0.290 1.548E-03 3.615E-02 IGHV3-11 ‒1.780 0.291 2.487E-04 1.016E-02 FASLG ‒1.779 0.291 1.466E-05 1.174E-03 NCAPG ‒1.772 0.293 2.036E-04 8.800E-03 LINC01560 ‒1.768 0.294 6.509E-04 1.979E-02 ZNF781 ‒1.755 0.296 4.745E-04 1.622E-02 IGHV1-18 ‒1.754 0.297 3.218E-05 2.164E-03 IGHJ3 ‒1.740 0.299 5.973E-04 1.886E-02 TRAV4 ‒1.727 0.302 1.912E-03 4.220E-02 IGKV1D-8 ‒1.722 0.303 1.633E-04 7.322E-03 TRGC2 ‒1.708 0.306 7.025E-09 1.773E-06 CUTALP ‒1.700 0.308 2.636E-04 1.060E-02 IGLV1-44 ‒1.699 0.308 8.700E-10 2.703E-07 AKAP6 ‒1.688 0.310 9.866E-04 2.625E-02 IGLV1-51 ‒1.669 0.314 8.440E-09 1.999E-06 ZNF181 ‒1.667 0.315 1.396E-05 1.123E-03 GIMAP4 ‒1.663 0.316 1.074E-06 1.281E-04 KLRK1 ‒1.654 0.318 1.775E-07 2.608E-05 SAMD9 ‒1.637 0.321 1.956E-06 2.156E-04 MMACHC ‒1.624 0.324 7.667E-05 4.227E-03 IGKV5-2 ‒1.617 0.326 7.368E-04 2.155E-02 THNSL1 ‒1.600 0.330 1.009E-03 2.665E-02 PDE4DIPP6 ‒1.599 0.330 3.369E-07 4.644E-05 ZNF658 ‒1.595 0.331 7.522E-05 4.176E-03 GIMAP7 ‒1.586 0.333 1.304E-03 3.220E-02 ZNF816 ‒1.571 0.337 1.156E-07 1.817E-05 ZNF772 ‒1.571 0.337 7.636E-09 1.834E-06 IGLV3-25 ‒1.563 0.338 1.939E-03 4.269E-02 ZNF501 ‒1.561 0.339 3.145E-04 1.211E-02 ENSG00000272913 ‒1.554 0.340 3.354E-04 1.260E-02 MOCS2-DT ‒1.552 0.341 2.297E-03 4.756E-02 SAMD9L ‒1.545 0.343 9.236E-04 2.521E-02 ZNF404 ‒1.543 0.343 4.938E-04 1.657E-02 ZNF470 ‒1.539 0.344 8.973E-05 4.727E-03 TAS2R4 ‒1.523 0.348 8.426E-04 2.381E-02 ENSG00000279696 ‒1.519 0.349 1.312E-05 1.061E-03 PAQR8 ‒1.516 0.350 1.029E-06 1.254E-04 ZNF594 ‒1.502 0.353 5.013E-04 1.666E-02 LINC02397 ‒1.500 0.354 2.194E-05 1.654E-03 IGLV8-61 ‒1.496 0.355 1.777E-07 2.608E-05 TIGD7 ‒1.494 0.355 2.569E-06 2.683E-04 IGKV1-39 ‒1.490 0.356 8.397E-06 7.511E-04 MOXD1 ‒1.490 0.356 8.500E-04 2.386E-02 CEP19 ‒1.480 0.358 2.381E-03 4.866E-02 KLRD1 ‒1.475 0.360 4.971E-04 1.662E-02 FRMPD3 ‒1.465 0.362 1.696E-05 1.326E-03 IGKV1-9 ‒1.457 0.364 1.158E-04 5.679E-03 ZNF780A ‒1.443 0.368 1.961E-06 2.156E-04 RTP4 ‒1.434 0.370 7.186E-04 2.128E-02 IGLV2-8 ‒1.433 0.370 5.396E-05 3.288E-03 BTN3A2 ‒1.431 0.371 1.402E-06 1.626E-04 TMEM60 ‒1.414 0.375 7.592E-04 2.192E-02 FAM111A-DT ‒1.389 0.382 3.412E-04 1.272E-02 ENSG00000279267 ‒1.387 0.382 2.038E-03 4.405E-02 SLAMF7 ‒1.384 0.383 2.446E-03 4.961E-02 GEMIN6 ‒1.375 0.386 1.182E-06 1.399E-04 IGKV2-30 ‒1.374 0.386 1.834E-04 8.071E-03 CASP4LP ‒1.370 0.387 2.150E-03 4.565E-02 JRKL ‒1.370 0.387 4.453E-04 1.535E-02 BTLA ‒1.366 0.388 3.303E-06 3.306E-04 ZNNT1 ‒1.364 0.388 1.516E-06 1.734E-04 ENSG00000246596 ‒1.363 0.389 2.840E-04 1.121E-02 UBE2T ‒1.361 0.389 1.501E-04 6.935E-03 ZBTB32 ‒1.356 0.391 2.469E-03 4.990E-02 EEF1AKNMT ‒1.356 0.391 2.746E-05 1.938E-03 IGHV3-33 ‒1.355 0.391 1.341E-04 6.372E-03 ENSG00000232611 ‒1.353 0.392 2.330E-03 4.784E-02 CXCR3 ‒1.350 0.392 3.158E-04 1.211E-02 CD200 ‒1.349 0.393 1.689E-04 7.535E-03 IGKV4-1 ‒1.347 0.393 9.343E-04 2.534E-02 DTX3L ‒1.342 0.394 5.186E-04 1.703E-02 IGHV1-46 ‒1.339 0.395 6.659E-05 3.835E-03 GCSAM ‒1.337 0.396 3.056E-05 2.096E-03 ZNF66 ‒1.325 0.399 5.140E-04 1.691E-02 GIMAP1 ‒1.324 0.399 7.225E-09 1.773E-06 AURKA ‒1.324 0.400 6.992E-04 2.096E-02 CENPBD1 ‒1.322 0.400 2.913E-04 1.144E-02 IL18RAP ‒1.309 0.404 1.963E-03 4.305E-02 NA ‒1.304 0.405 2.527E-09 7.081E-07 ZNF737 ‒1.302 0.406 5.127E-04 1.690E-02 IGLV2-23 ‒1.300 0.406 3.615E-04 1.324E-02 IGLV3-27 ‒1.298 0.407 1.261E-03 3.136E-02 PGBD2 ‒1.296 0.407 8.355E-06 7.511E-04 IGKV1-12 ‒1.292 0.409 5.242E-07 6.996E-05 IGKV1-16 ‒1.291 0.409 1.932E-05 1.477E-03 DENND2D ‒1.283 0.411 3.314E-05 2.202E-03 IGKV3-11 ‒1.281 0.412 3.948E-07 5.354E-05 NA ‒1.279 0.412 9.526E-04 2.571E-02 CMTR2 ‒1.273 0.414 7.274E-08 1.199E-05 BBS10 ‒1.266 0.416 1.207E-03 3.041E-02 FIGNL1 ‒1.265 0.416 1.068E-06 1.281E-04 IGLV3-1 ‒1.264 0.416 9.491E-04 2.566E-02 ARSK ‒1.263 0.417 4.091E-05 2.626E-03 IGLV1-47 ‒1.258 0.418 8.770E-04 2.430E-02 ZKSCAN7 ‒1.242 0.423 8.287E-04 2.354E-02 IGKV3-15 ‒1.240 0.423 4.808E-05 2.994E-03 HCP5 ‒1.238 0.424 2.807E-05 1.966E-03 TMED2-DT ‒1.231 0.426 1.984E-03 4.328E-02 C14orf119 ‒1.227 0.427 6.280E-04 1.941E-02 ZFP3 ‒1.218 0.430 5.653E-05 3.383E-03 ZNF583 ‒1.216 0.430 5.982E-04 1.886E-02 IGLC2 ‒1.212 0.432 1.360E-03 3.330E-02 TMEM140 ‒1.207 0.433 1.390E-03 3.373E-02 ZNF613 ‒1.202 0.435 1.454E-03 3.459E-02 ACKR3 ‒1.202 0.435 1.373E-04 6.451E-03 ZNF780B ‒1.201 0.435 3.300E-04 1.249E-02 IGKV3-20 ‒1.198 0.436 1.620E-04 7.318E-03 ZNF626 ‒1.191 0.438 1.015E-03 2.674E-02 ZNF607 ‒1.184 0.440 1.295E-05 1.052E-03 ZNF175 ‒1.181 0.441 2.765E-06 2.853E-04 LRIF1 ‒1.178 0.442 2.817E-04 1.117E-02 STAT1 ‒1.175 0.443 1.256E-03 3.134E-02 TRGC1 ‒1.175 0.443 7.599E-05 4.203E-03 RBM12B ‒1.174 0.443 7.139E-06 6.560E-04 IGLV2-11 ‒1.166 0.446 1.560E-03 3.629E-02 GIMAP6 ‒1.163 0.447 2.190E-04 9.323E-03 IGKV1-5 ‒1.159 0.448 1.131E-05 9.558E-04 MRPL35 ‒1.159 0.448 1.822E-05 1.399E-03 ZNF721 ‒1.157 0.449 2.130E-07 3.088E-05 ZNF799 ‒1.155 0.449 1.154E-03 2.937E-02 CARD8-AS1 ‒1.154 0.449 6.959E-04 2.090E-02 ZNF665 ‒1.152 0.450 3.676E-04 1.338E-02 ZNF226 ‒1.150 0.450 5.285E-09 1.411E-06 ZNF616 ‒1.147 0.451 1.652E-03 3.821E-02 LXN ‒1.145 0.452 6.716E-04 2.028E-02 IGLV4-69 ‒1.138 0.455 1.009E-03 2.665E-02 C5orf51 ‒1.132 0.456 1.835E-03 4.104E-02 FCRL3 ‒1.127 0.458 2.841E-04 1.121E-02 MYBL1 ‒1.127 0.458 9.251E-04 2.521E-02 TIGD2 ‒1.118 0.461 4.773E-04 1.627E-02 IL18R1 ‒1.117 0.461 1.725E-03 3.947E-02 LBH ‒1.117 0.461 4.585E-05 2.866E-03 ENSG00000279059 ‒1.114 0.462 1.704E-03 3.916E-02 ENSG00000259877 ‒1.113 0.462 8.156E-04 2.324E-02 ZNF189 ‒1.100 0.467 6.862E-04 2.068E-02 C17orf80 ‒1.096 0.468 9.718E-06 8.380E-04 PREPL ‒1.095 0.468 5.271E-04 1.721E-02 ZKSCAN3 ‒1.094 0.468 2.583E-04 1.047E-02 OGFOD1 ‒1.094 0.468 1.696E-04 7.547E-03 ZBTB38 ‒1.090 0.470 1.106E-03 2.849E-02 N6AMT1 ‒1.087 0.471 8.993E-04 2.471E-02 NAPEPLD ‒1.084 0.472 1.109E-03 2.853E-02 INTS5 ‒1.080 0.473 4.717E-06 4.533E-04 IGKC ‒1.079 0.473 7.877E-04 2.253E-02 GIMAP8 ‒1.076 0.474 9.667E-06 8.379E-04 ABCB1 ‒1.073 0.475 7.390E-04 2.158E-02 TRDC ‒1.073 0.475 2.020E-03 4.378E-02 ZNF230 ‒1.072 0.476 9.037E-05 4.734E-03 UMPS ‒1.071 0.476 2.068E-05 1.574E-03 ZNF681 ‒1.067 0.477 2.312E-03 4.767E-02 SLC25A20 ‒1.067 0.477 1.269E-05 1.036E-03 RNASEL ‒1.063 0.479 1.762E-03 4.014E-02 MCM8 ‒1.062 0.479 9.754E-05 5.016E-03 PCDH9 ‒1.059 0.480 5.797E-04 1.839E-02 MRPL50 ‒1.055 0.481 2.564E-04 1.042E-02 HIBCH ‒1.048 0.484 6.758E-06 6.245E-04 HERPUD2-AS1 ‒1.043 0.485 1.263E-03 3.137E-02 LOC101927151 ‒1.040 0.486 1.764E-03 4.014E-02 SLAMF6 ‒1.038 0.487 9.397E-06 8.187E-04 L3MBTL3 ‒1.023 0.492 1.079E-04 5.384E-03 SP4 ‒1.022 0.492 1.445E-03 3.448E-02 ZNF397 ‒1.019 0.494 2.382E-07 3.409E-05 WEE1 ‒1.017 0.494 3.585E-04 1.319E-02 PURA ‒1.015 0.495 1.806E-05 1.393E-03 ENSG00000259820 ‒1.010 0.497 1.386E-03 3.367E-02 TTC9C ‒1.006 0.498 4.920E-05 3.031E-03 IGLV2-14 ‒1.003 0.499 4.237E-04 1.478E-02 SIT1 ‒1.001 0.500 6.669E-04 2.017E-02 CHURC1 ‒1.000 0.500 7.051E-04 2.104E-02 ZNF234 ‒0.996 0.501 6.351E-04 1.956E-02 UTP14C ‒0.995 0.502 2.641E-04 1.060E-02 GTF2E1 ‒0.994 0.502 4.997E-04 1.666E-02 LPAR6 ‒0.983 0.506 6.115E-04 1.909E-02 CEACAM1 ‒0.981 0.507 7.600E-04 2.192E-02 GSDMB ‒0.980 0.507 2.299E-04 9.642E-03 PM20D2 ‒0.974 0.509 4.898E-05 3.028E-03 ALDH5A1 ‒0.969 0.511 1.091E-03 2.826E-02 CPT1A ‒0.965 0.512 4.082E-04 1.439E-02 KCTD11 ‒0.963 0.513 2.092E-04 8.998E-03 DHFR2 ‒0.962 0.513 4.011E-04 1.423E-02 YIPF4 ‒0.961 0.514 5.389E-06 5.063E-04 ENSG00000260719 ‒0.957 0.515 1.277E-04 6.170E-03 C21orf91 ‒0.954 0.516 3.112E-04 1.211E-02 TRNT1 ‒0.948 0.518 2.113E-04 9.062E-03 TMEM186 ‒0.946 0.519 9.766E-04 2.615E-02 SPDL1 ‒0.939 0.522 9.564E-04 2.577E-02 ZFP82 ‒0.919 0.529 8.385E-04 2.374E-02 DARS2 ‒0.918 0.529 1.614E-03 3.744E-02 PAXIP1-AS2 ‒0.906 0.534 8.944E-04 2.466E-02 MRM1 ‒0.895 0.538 5.773E-04 1.839E-02 PYGO2 ‒0.891 0.539 3.044E-05 2.096E-03 IRF4 ‒0.888 0.540 2.427E-03 4.942E-02 ZNF486 ‒0.888 0.540 6.370E-04 1.958E-02 PRAG1 ‒0.888 0.540 7.519E-04 2.176E-02 ZNF320 ‒0.887 0.541 9.588E-04 2.580E-02 GGPS1 ‒0.883 0.542 1.508E-05 1.202E-03 TRMT13 ‒0.875 0.545 7.919E-05 4.282E-03 ZNF420 ‒0.873 0.546 1.863E-03 4.134E-02 FBXO22 ‒0.872 0.546 3.694E-05 2.398E-03 ENSG00000268027 ‒0.866 0.549 1.188E-03 3.010E-02 NUP43 ‒0.865 0.549 1.418E-03 3.406E-02 TIA1 ‒0.862 0.550 1.475E-06 1.699E-04 ZNF785 ‒0.862 0.550 2.190E-03 4.638E-02 ZNF480 ‒0.861 0.550 4.853E-05 3.011E-03 ZNF260 ‒0.856 0.552 2.416E-03 4.924E-02 MAT2B ‒0.853 0.554 1.065E-05 9.093E-04 RAB29 ‒0.845 0.557 4.962E-04 1.662E-02 LEO1 ‒0.845 0.557 5.540E-05 3.327E-03 GIMAP2 ‒0.844 0.557 1.041E-03 2.714E-02 ZNF74 ‒0.843 0.557 1.478E-03 3.501E-02 ZNF200 ‒0.836 0.560 2.650E-05 1.896E-03 FGFR1OP2 ‒0.833 0.561 3.555E-05 2.354E-03 PABIR1 ‒0.833 0.561 9.817E-04 2.620E-02 KLHL9 ‒0.829 0.563 1.518E-03 3.569E-02 HSPA8 ‒0.828 0.563 3.539E-04 1.308E-02 THAP5 ‒0.828 0.563 1.208E-03 3.041E-02 PPIL1 ‒0.824 0.565 2.268E-03 4.732E-02 FANCF ‒0.817 0.568 1.850E-03 4.121E-02 STT3A ‒0.810 0.570 2.334E-04 9.667E-03 VKORC1L1 ‒0.800 0.574 2.362E-03 4.832E-02 CTR9 ‒0.800 0.574 8.579E-04 2.400E-02 UBE4A ‒0.799 0.575 1.130E-04 5.605E-03 IRF1-AS1 ‒0.797 0.576 2.316E-03 4.767E-02 RBM4B ‒0.795 0.576 5.011E-04 1.666E-02 KCTD21 ‒0.795 0.576 2.442E-03 4.961E-02 RPE ‒0.793 0.577 4.809E-04 1.630E-02 UBA6-AS1 ‒0.787 0.580 1.551E-04 7.125E-03 POLH ‒0.778 0.583 2.054E-03 4.417E-02 TMEM223 ‒0.775 0.584 1.512E-03 3.561E-02 ZNF561 ‒0.772 0.586 1.749E-03 3.995E-02 TRIM4 ‒0.769 0.587 7.730E-05 4.234E-03 ZNF557 ‒0.765 0.589 2.316E-03 4.767E-02 FCMR ‒0.762 0.590 2.407E-06 2.546E-04 ZKSCAN1 ‒0.759 0.591 4.671E-04 1.600E-02 ENSG00000239665 ‒0.757 0.592 5.955E-05 3.526E-03 EIF2S1 ‒0.752 0.594 6.725E-05 3.860E-03 C15orf40 ‒0.751 0.594 6.441E-04 1.966E-02 ZNF154 ‒0.749 0.595 6.572E-04 1.995E-02 BRD8 ‒0.748 0.595 2.083E-05 1.578E-03 ARCN1 ‒0.748 0.595 1.313E-04 6.280E-03 ERGIC2 ‒0.741 0.598 6.239E-04 1.935E-02 FASTKD1 ‒0.737 0.600 7.642E-04 2.200E-02 ZNF146 ‒0.736 0.600 1.282E-03 3.172E-02 ZNF841 ‒0.736 0.601 2.956E-04 1.159E-02 TRIM27 ‒0.736 0.601 1.358E-04 6.399E-03 KRBOX4 ‒0.729 0.603 3.577E-04 1.319E-02 HSPH1 ‒0.713 0.610 1.531E-03 3.587E-02 NCOR1 ‒0.713 0.610 1.901E-03 4.202E-02 HNRNPF ‒0.713 0.610 1.906E-04 8.346E-03 COL19A1 ‒0.699 0.616 2.265E-03 4.732E-02 MON2 ‒0.686 0.622 2.158E-03 4.576E-02 MITD1 ‒0.684 0.622 3.227E-04 1.233E-02 ATAD2B ‒0.679 0.624 1.235E-03 3.092E-02 TUBGCP4 ‒0.676 0.626 5.429E-04 1.762E-02 MRPS14 ‒0.674 0.627 2.343E-03 4.805E-02 GLS ‒0.673 0.627 1.256E-03 3.134E-02 VEZT ‒0.668 0.629 2.260E-03 4.732E-02 TARS1 ‒0.653 0.636 1.282E-04 6.179E-03 PIK3R4 ‒0.641 0.641 2.285E-03 4.740E-02 OBI1 ‒0.641 0.641 2.286E-03 4.740E-02 ZNF671 ‒0.635 0.644 1.380E-03 3.359E-02 LINC00667 ‒0.635 0.644 6.179E-04 1.924E-02 MCM3 ‒0.626 0.648 3.529E-04 1.307E-02 PIGF ‒0.612 0.654 2.230E-03 4.694E-02 THRAP3 ‒0.604 0.658 1.783E-04 7.869E-03 PLRG1 ‒0.599 0.660 2.278E-03 4.736E-02 APOL2 ‒0.596 0.662 1.351E-03 3.318E-02 GART ‒0.591 0.664 2.004E-03 4.359E-02 NUP42 ‒0.588 0.665 1.143E-03 2.922E-02 ZNF559 ‒0.587 0.666 8.986E-04 2.471E-02 ZNF362 0.588 1.503 2.457E-03 4.978E-02 WBP11 0.591 1.506 1.572E-03 3.652E-02 MAPRE1 0.593 1.509 1.099E-03 2.834E-02 INSIG1 0.599 1.515 1.037E-03 2.711E-02 CCNY 0.602 1.517 7.865E-04 2.253E-02 JARID2 0.621 1.537 1.219E-03 3.059E-02 FBRS 0.622 1.539 3.948E-04 1.404E-02 MAPK1IP1L 0.625 1.542 1.989E-03 4.332E-02 RBM3 0.629 1.547 1.531E-03 3.587E-02 CSGALNACT2 0.632 1.549 1.552E-03 3.615E-02 INTS1 0.646 1.565 1.496E-03 3.529E-02 HNRNPH2 0.649 1.568 3.683E-04 1.338E-02 TMEM167B 0.655 1.575 3.365E-04 1.260E-02 LAPTM5 0.655 1.575 4.076E-04 1.439E-02 MLF2 0.660 1.581 1.411E-03 3.403E-02 CHCHD2 0.660 1.581 1.233E-03 3.090E-02 RREB1 0.661 1.581 9.899E-05 5.044E-03 TMCC1 0.663 1.584 2.444E-03 4.961E-02 EME2 0.664 1.584 6.241E-04 1.935E-02 TRA2B 0.664 1.584 8.481E-04 2.385E-02 RAB1A 0.669 1.590 4.183E-04 1.469E-02 UBC 0.676 1.597 5.208E-05 3.196E-03 NCOR2 0.677 1.599 1.943E-03 4.272E-02 DAZAP2 0.677 1.599 5.074E-04 1.680E-02 ARF1 0.681 1.603 8.186E-05 4.398E-03 ADIPOR1 0.685 1.608 9.716E-05 5.012E-03 EIF5A 0.685 1.608 1.589E-04 7.222E-03 MKNK2 0.688 1.611 1.371E-03 3.345E-02 RAPGEF2 0.691 1.614 4.612E-04 1.583E-02 HNRNPA0 0.691 1.614 1.675E-03 3.854E-02 TET3 0.692 1.615 1.974E-03 4.317E-02 HNRNPL 0.693 1.617 1.246E-05 1.022E-03 MAP1LC3B 0.694 1.618 8.722E-05 4.627E-03 RPS9 0.707 1.633 2.099E-03 4.490E-02 RHBDD2 0.711 1.637 1.781E-03 4.030E-02 SLC25A3 0.715 1.641 6.243E-05 3.645E-03 SYF2 0.719 1.646 1.787E-03 4.033E-02 OTULINL 0.726 1.654 8.728E-04 2.426E-02 ENSG00000279117 0.734 1.664 1.777E-03 4.028E-02 RNF26 0.746 1.677 9.815E-04 2.620E-02 PAFAH1B2 0.748 1.680 1.165E-04 5.695E-03 HERPUD1 0.750 1.682 1.949E-04 8.511E-03 RSL24D1 0.752 1.684 1.096E-03 2.830E-02 MCL1 0.752 1.685 1.803E-03 4.054E-02 MRFAP1 0.755 1.688 1.623E-04 7.318E-03 PNRC1 0.762 1.696 8.879E-04 2.452E-02 SUMO3 0.765 1.700 2.090E-04 8.998E-03 BUD31 0.776 1.712 1.796E-03 4.049E-02 SLC25A33 0.790 1.729 1.775E-03 4.028E-02 COX4I1 0.792 1.732 3.267E-04 1.246E-02 ANXA1 0.793 1.732 7.262E-04 2.138E-02 AP1G2-AS1 0.796 1.736 1.838E-04 8.071E-03 SRF 0.798 1.739 1.130E-03 2.892E-02 MMP24OS 0.799 1.739 1.058E-04 5.309E-03 CYP4V2 0.799 1.740 1.630E-04 7.322E-03 BCL7B 0.801 1.743 3.883E-04 1.392E-02 PNPLA2 0.803 1.745 6.248E-04 1.935E-02 TGIF1 0.809 1.752 7.705E-05 4.234E-03 SNN 0.811 1.754 2.741E-04 1.095E-02 UAP1L1 0.819 1.764 7.464E-04 2.172E-02 EEPD1 0.831 1.778 3.783E-04 1.368E-02 TRAF4 0.847 1.798 4.790E-04 1.627E-02 CARD19 0.849 1.801 5.571E-04 1.789E-02 TUBB4B 0.850 1.802 1.602E-05 1.264E-03 ADGRL1-AS1 0.863 1.818 1.448E-03 3.448E-02 CLK1 0.869 1.826 2.140E-03 4.555E-02 IRF1 0.870 1.828 9.341E-06 8.187E-04 SLC3A2 0.876 1.835 1.523E-04 7.017E-03 RNF19B 0.876 1.836 1.819E-03 4.085E-02 IDI1 0.876 1.836 4.200E-06 4.154E-04 KLHL26 0.888 1.850 4.394E-04 1.522E-02 VAMP3 0.888 1.850 3.411E-04 1.272E-02 ETF1 0.889 1.852 9.769E-07 1.208E-04 AKT1S1 0.892 1.856 2.312E-05 1.705E-03 MAPK7 0.892 1.856 2.053E-03 4.417E-02 CDKN2D 0.893 1.857 3.615E-05 2.374E-03 EIF1B 0.894 1.859 8.468E-04 2.385E-02 SNIP1 0.895 1.859 1.426E-04 6.675E-03 TMEM201 0.896 1.861 4.790E-04 1.627E-02 DDX21 0.902 1.869 3.152E-05 2.138E-03 NECAP1 0.902 1.869 1.724E-06 1.920E-04 VPS18 0.905 1.873 6.841E-05 3.890E-03 RFX2 0.910 1.879 1.151E-03 2.932E-02 MEF2D 0.911 1.881 8.729E-09 2.039E-06 SIVA1 0.915 1.886 2.287E-05 1.694E-03 ATXN1L 0.915 1.886 6.338E-06 5.888E-04 ANAPC15 0.924 1.897 2.563E-04 1.042E-02 CDK2AP1 0.930 1.905 1.783E-03 4.030E-02 MED30 0.930 1.905 4.214E-04 1.473E-02 PRNP 0.930 1.906 1.267E-04 6.138E-03 CDKN1B 0.932 1.907 1.403E-03 3.389E-02 TENT5C 0.933 1.909 4.399E-04 1.522E-02 PI4K2A 0.937 1.914 3.144E-04 1.211E-02 ENSG00000280138 0.939 1.917 9.366E-06 8.187E-04 TUBA1C 0.941 1.920 1.147E-04 5.658E-03 UPP1 0.945 1.925 2.448E-04 1.004E-02 DENND1A 0.946 1.926 2.786E-04 1.110E-02 GCNT2 0.948 1.929 1.830E-03 4.097E-02 SELENOK 0.953 1.936 5.480E-05 3.305E-03 PTS 0.964 1.951 3.127E-04 1.211E-02 RBM7 0.974 1.964 2.460E-03 4.979E-02 PRXL2C 0.980 1.973 1.258E-03 3.134E-02 TWF1 0.986 1.980 1.977E-04 8.612E-03 ATF4 0.990 1.987 3.687E-05 2.398E-03 ENSG00000269688 0.993 1.991 3.432E-04 1.277E-02 WDR74 1.000 2.000 5.483E-05 3.305E-03 GPR35 1.001 2.001 1.053E-06 1.274E-04 RNF103 1.004 2.006 5.484E-04 1.770E-02 EMD 1.005 2.008 2.369E-05 1.725E-03 MGST3 1.014 2.020 5.682E-04 1.816E-02 JMJD6 1.015 2.021 7.918E-05 4.282E-03 GRPEL1 1.016 2.023 2.361E-06 2.513E-04 CCRL2 1.018 2.025 1.023E-03 2.693E-02 CTIF 1.019 2.026 8.366E-04 2.372E-02 NFKBIB 1.024 2.034 3.801E-04 1.372E-02 MNT 1.033 2.046 7.009E-05 3.955E-03 TOM1 1.042 2.059 1.475E-03 3.497E-02 TLE3 1.044 2.062 3.236E-06 3.258E-04 JOSD1 1.044 2.062 3.044E-04 1.190E-02 FCGRT 1.046 2.065 1.830E-03 4.097E-02 EIF5 1.048 2.068 2.865E-08 5.537E-06 NXT1 1.050 2.071 1.717E-05 1.336E-03 ARHGDIA 1.052 2.073 3.600E-04 1.322E-02 BRI3 1.054 2.076 2.099E-03 4.490E-02 NDUFV2 1.060 2.085 9.459E-04 2.561E-02 CLN8-AS1 1.063 2.090 2.094E-03 4.490E-02 FEM1C 1.065 2.092 2.259E-04 9.522E-03 NR1H2 1.067 2.095 3.494E-04 1.297E-02 FASTKD5 1.092 2.131 1.315E-04 6.280E-03 YOD1 1.093 2.134 1.716E-03 3.931E-02 PTGER4 1.096 2.138 2.812E-06 2.884E-04 SMURF1 1.097 2.139 4.288E-06 4.168E-04 CCNL1 1.102 2.147 5.947E-09 1.562E-06 LDLR 1.106 2.152 3.636E-05 2.379E-03 SLC22A18 1.107 2.154 2.273E-03 4.736E-02 IRGQ 1.115 2.166 1.200E-03 3.035E-02 CHASERR 1.116 2.167 1.599E-04 7.247E-03 HMGB3 1.118 2.170 2.043E-03 4.409E-02 IER5 1.119 2.172 1.609E-06 1.816E-04 EIF2AK3-DT 1.120 2.174 2.237E-03 4.703E-02 TUBB2A 1.122 2.177 7.424E-04 2.164E-02 PDE4B 1.123 2.178 1.433E-04 6.675E-03 ADAM9 1.127 2.184 5.438E-04 1.762E-02 GPR183 1.127 2.184 1.572E-06 1.786E-04 CKAP4 1.128 2.185 1.157E-04 5.679E-03 KLF11 1.128 2.186 3.067E-05 2.096E-03 ZMIZ1 1.129 2.187 9.055E-04 2.480E-02 RBM34 1.132 2.192 1.973E-03 4.317E-02 KCNQ1 1.132 2.192 5.875E-07 7.599E-05 GDPD5 1.136 2.197 6.395E-04 1.959E-02 C6orf226 1.136 2.198 7.171E-04 2.127E-02 MFSD2A 1.137 2.199 1.225E-04 5.954E-03 BACH1 1.140 2.204 2.817E-04 1.117E-02 MYLIP 1.143 2.209 9.289E-06 8.187E-04 RELL1 1.151 2.220 5.583E-04 1.789E-02 EIF1 1.159 2.234 1.296E-07 2.017E-05 SLC7A5 1.160 2.234 1.919E-03 4.230E-02 ATP6V0C 1.168 2.247 3.262E-05 2.177E-03 YRDC 1.169 2.249 6.586E-08 1.119E-05 DDX47 1.173 2.254 1.445E-03 3.448E-02 CPNE2 1.173 2.255 2.342E-05 1.712E-03 CCDC59 1.176 2.260 2.328E-04 9.667E-03 ENSG00000258944 1.181 2.267 2.202E-03 4.652E-02 H3-3B 1.182 2.269 2.639E-04 1.060E-02 GPX1 1.182 2.270 1.148E-03 2.930E-02 ZFAND2A 1.187 2.277 2.136E-06 2.333E-04 RAPH1 1.198 2.294 1.846E-03 4.116E-02 CBX4 1.204 2.304 2.524E-10 9.430E-08 PRR7 1.219 2.328 2.186E-04 9.323E-03 MAFK 1.221 2.332 6.495E-08 1.119E-05 KIAA1522 1.227 2.340 7.294E-05 4.075E-03 FTH1 1.227 2.341 1.395E-03 3.380E-02 GABARAPL1 1.229 2.344 6.533E-08 1.119E-05 PELI1 1.232 2.349 4.744E-08 8.398E-06 IRF2BP2 1.236 2.356 2.639E-11 1.082E-08 ENSG00000255847 1.243 2.367 2.218E-05 1.658E-03 SULT1A1 1.245 2.370 2.045E-03 4.409E-02 KLF6 1.245 2.371 2.311E-04 9.642E-03 DUS3L 1.255 2.387 1.237E-05 1.020E-03 PIGA 1.265 2.404 1.580E-05 1.253E-03 TUBA1A 1.269 2.410 4.847E-04 1.640E-02 RNF139 1.270 2.412 9.661E-04 2.595E-02 OAF 1.272 2.415 1.378E-03 3.358E-02 ADCY9 1.284 2.435 3.922E-04 1.397E-02 TIPARP 1.293 2.451 7.424E-06 6.748E-04 CEBPB 1.296 2.456 2.245E-03 4.711E-02 ENSG00000262766 1.307 2.474 2.312E-03 4.767E-02 PTPRE 1.316 2.490 6.628E-04 2.008E-02 PMAIP1 1.317 2.492 6.762E-07 8.680E-05 NRROS 1.319 2.495 9.700E-05 5.012E-03 CBX6 1.319 2.495 1.784E-07 2.608E-05 BCL10 1.322 2.499 1.566E-08 3.292E-06 RIPK2 1.323 2.502 1.029E-03 2.698E-02 YPEL5 1.324 2.504 2.780E-07 3.895E-05 SIAH1 1.328 2.511 2.318E-04 9.648E-03 RELT 1.329 2.513 1.116E-03 2.863E-02 NA 1.330 2.513 2.400E-03 4.897E-02 MAFG 1.331 2.515 1.962E-08 3.966E-06 POLR1F 1.337 2.527 5.113E-06 4.858E-04 ZBTB21 1.342 2.535 5.950E-05 3.526E-03 GZF1 1.342 2.535 4.131E-10 1.478E-07 MCEMP1 1.347 2.543 1.265E-03 3.137E-02 SNHG15 1.357 2.561 3.176E-10 1.161E-07 EIF4A1 1.357 2.561 9.866E-09 2.242E-06 C5AR1 1.374 2.592 1.495E-03 3.529E-02 FBXO33 1.377 2.598 1.552E-03 3.615E-02 PLPPR2 1.384 2.611 5.988E-04 1.886E-02 ZNF628 1.389 2.619 6.461E-05 3.759E-03 OSER1 1.392 2.625 1.015E-08 2.277E-06 SIRPA 1.395 2.630 1.520E-03 3.571E-02 KDM6B 1.404 2.646 3.228E-08 6.099E-06 SRGN 1.408 2.653 7.075E-05 3.979E-03 DGCR11 1.413 2.663 2.472E-03 4.990E-02 HNRNPD-DT 1.414 2.665 8.446E-04 2.383E-02 SPATA2 1.416 2.668 7.274E-09 1.773E-06 CD69 1.416 2.669 4.169E-04 1.466E-02 RBM38 1.425 2.685 1.195E-05 9.982E-04 ZNF394 1.426 2.688 3.509E-08 6.485E-06 ANKRD9 1.427 2.690 5.212E-04 1.708E-02 RBM47 1.431 2.696 3.906E-04 1.394E-02 B3GNT7 1.433 2.700 2.744E-05 1.938E-03 EAF1 1.438 2.709 3.380E-14 2.842E-11 PTP4A1 1.442 2.717 4.180E-07 5.624E-05 MXD1 1.447 2.727 3.820E-04 1.376E-02 BNIP1 1.448 2.729 5.154E-06 4.869E-04 ETS2 1.449 2.729 5.042E-04 1.672E-02 HIF1A 1.457 2.745 9.755E-09 2.242E-06 TOE1 1.468 2.766 4.288E-05 2.731E-03 CLP1 1.468 2.766 8.330E-08 1.347E-05 ENSG00000260708 1.477 2.783 6.458E-04 1.967E-02 DUSP5 1.477 2.783 5.683E-11 2.209E-08 C17orf49 1.479 2.787 5.141E-10 1.729E-07 MYADM 1.491 2.810 3.961E-06 3.941E-04 SERTAD1 1.491 2.811 5.429E-06 5.072E-04 SERTAD3 1.498 2.825 7.674E-08 1.253E-05 TTC34 1.499 2.826 3.359E-04 1.260E-02 NFKBID 1.499 2.826 1.296E-04 6.227E-03 ENSG00000279602 1.499 2.827 4.282E-06 4.168E-04 LDLRAD3 1.516 2.861 2.247E-03 4.711E-02 CRABP2 1.524 2.877 1.358E-03 3.330E-02 ZP3 1.525 2.878 2.169E-04 9.279E-03 SMARCD3 1.525 2.878 1.459E-03 3.466E-02 MMP14 1.527 2.882 2.038E-03 4.405E-02 SDE2 1.533 2.893 4.053E-08 7.328E-06 GLT1D1 1.536 2.900 1.483E-03 3.506E-02 F5 1.539 2.907 1.117E-03 2.863E-02 H2BC21 1.547 2.921 4.282E-04 1.491E-02 CEACAM19 1.547 2.923 2.489E-04 1.016E-02 ENSG00000277879 1.551 2.930 1.364E-03 3.334E-02 DUSP1 1.554 2.936 3.121E-04 1.211E-02 ARRDC4 1.555 2.938 1.240E-08 2.707E-06 OTUD1 1.561 2.950 9.380E-05 4.868E-03 STX11 1.567 2.963 9.889E-05 5.044E-03 RNVU1-30 1.568 2.966 8.028E-04 2.292E-02 VENTX 1.576 2.981 2.028E-04 8.796E-03 JDP2 1.578 2.986 5.716E-07 7.451E-05 SOX4 1.591 3.013 4.929E-04 1.657E-02 RBM38-AS1 1.594 3.018 1.567E-04 7.159E-03 HIC1 1.595 3.020 4.478E-06 4.328E-04 BTG3 1.596 3.024 7.075E-04 2.106E-02 LINC00963 1.597 3.025 1.758E-03 4.012E-02 NRGN 1.599 3.029 1.192E-04 5.809E-03 CXCR4 1.600 3.032 5.429E-08 9.511E-06 UBE2FP1 1.607 3.047 8.372E-05 4.469E-03 DUSP10 1.612 3.056 5.420E-05 3.290E-03 MTSS2 1.615 3.064 8.435E-10 2.676E-07 STAB1 1.617 3.068 1.627E-03 3.768E-02 LONRF3 1.619 3.071 1.771E-04 7.835E-03 IER5L 1.625 3.084 4.887E-06 4.669E-04 SH3RF1 1.630 3.096 3.304E-04 1.249E-02 NIBAN2 1.653 3.144 1.078E-04 5.384E-03 SBDS 1.653 3.146 5.381E-07 7.069E-05 ZC3H12A 1.654 3.148 1.620E-13 1.048E-10 LOC102723996 1.667 3.175 1.768E-03 4.018E-02 TNRC18P1 1.675 3.194 7.768E-04 2.229E-02 FAM20C 1.692 3.232 3.151E-04 1.211E-02 JUND 1.705 3.261 4.856E-10 1.701E-07 CSF3R 1.718 3.291 1.421E-03 3.409E-02 BTG2 1.727 3.310 1.556E-04 7.131E-03 AHR 1.735 3.328 5.842E-05 3.483E-03 GGTA1 1.740 3.341 2.319E-03 4.767E-02 SKOR1 1.742 3.346 1.901E-03 4.202E-02 GADD45A 1.743 3.347 1.157E-05 9.729E-04 MIR222HG 1.747 3.356 9.930E-05 5.045E-03 MIDN 1.749 3.361 4.288E-05 2.731E-03 ZBTB10 1.750 3.363 1.332E-04 6.346E-03 KLF10 1.753 3.371 2.696E-04 1.079E-02 RAB3A 1.758 3.383 7.505E-04 2.176E-02 HES1 1.759 3.384 4.456E-04 1.535E-02 SNORA75 1.760 3.388 1.416E-03 3.406E-02 FSCN1 1.760 3.388 4.913E-04 1.656E-02 ENSG00000275056 1.761 3.390 2.029E-04 8.796E-03 JAG1 1.768 3.405 8.961E-05 4.727E-03 GNA15 1.785 3.446 2.928E-06 2.966E-04 ADM 1.791 3.461 6.120E-04 1.909E-02 MGP 1.792 3.463 2.357E-03 4.828E-02 JUNB 1.800 3.482 1.334E-08 2.841E-06 NINJ1 1.804 3.492 3.508E-08 6.485E-06 CCR1 1.810 3.507 3.162E-04 1.211E-02 COL9A3 1.812 3.510 1.799E-03 4.050E-02 ENSG00000280067 1.814 3.516 9.222E-04 2.521E-02 RPL32P1 1.820 3.532 8.565E-04 2.400E-02 GAS2L1 1.832 3.560 3.706E-04 1.343E-02 NFKBIE 1.850 3.604 1.032E-08 2.283E-06 NOCT 1.851 3.607 2.854E-05 1.991E-03 SMOX 1.852 3.610 5.454E-04 1.764E-02 SLC6A8 1.859 3.628 1.896E-03 4.200E-02 RGS2 1.860 3.630 1.027E-05 8.808E-04 ENSG00000272256 1.876 3.670 8.199E-04 2.333E-02 S100A8 1.880 3.681 3.006E-05 2.080E-03 LMNA 1.891 3.710 4.578E-08 8.190E-06 KLF4 1.906 3.748 3.816E-05 2.459E-03 JUN 1.909 3.754 1.266E-08 2.729E-06 PDGFC 1.912 3.764 1.164E-03 2.952E-02 EREG 1.914 3.769 3.635E-04 1.328E-02 SLC22A4 1.916 3.775 1.061E-03 2.763E-02 ITPRIP 1.918 3.778 4.358E-14 3.490E-11 BHLHE40 1.918 3.780 1.442E-07 2.204E-05 CDKN1A 1.920 3.784 2.221E-06 2.395E-04 GADD45B 1.925 3.797 1.663E-08 3.410E-06 IER2 1.926 3.801 1.071E-05 9.093E-04 RETN 1.937 3.828 4.254E-06 4.168E-04 P2RY2 1.943 3.846 1.003E-03 2.657E-02 CD14 1.953 3.872 2.367E-04 9.780E-03 TNFAIP3 1.956 3.881 4.405E-05 2.795E-03 RASGEF1B 1.958 3.885 6.554E-05 3.801E-03 VEGFA 1.967 3.909 2.005E-08 3.966E-06 DDIT3 1.973 3.925 3.717E-15 4.167E-12 ENSG00000232811 1.978 3.940 2.881E-06 2.937E-04 LRG1 1.979 3.943 1.737E-04 7.707E-03 ARHGAP22 1.979 3.943 6.293E-04 1.942E-02 IGHEP2 1.988 3.966 5.389E-04 1.756E-02 ENSG00000279520 1.994 3.984 4.254E-16 5.503E-13 RHBDL1 2.002 4.005 7.004E-04 2.096E-02 BTBD19 2.014 4.040 2.229E-04 9.444E-03 HOMER3 2.017 4.047 9.268E-05 4.825E-03 ENC1 2.022 4.063 2.181E-06 2.366E-04 ENSG00000273972 2.030 4.084 1.666E-03 3.837E-02 RGS17P1 2.048 4.135 1.199E-05 9.982E-04 S100A9 2.049 4.137 8.698E-06 7.739E-04 FOS 2.056 4.159 7.651E-07 9.674E-05 ENSG00000270640 2.067 4.190 1.267E-03 3.137E-02 SNAI1 2.070 4.200 1.332E-03 3.280E-02 LRP3 2.087 4.249 6.814E-05 3.890E-03 KCNK7 2.089 4.253 3.744E-05 2.421E-03 IFITM10 2.095 4.273 3.236E-05 2.168E-03 NECTIN2 2.118 4.342 3.293E-04 1.249E-02 SCN1B 2.129 4.374 7.524E-05 4.176E-03 S100A12 2.131 4.380 7.126E-05 3.994E-03 NRARP 2.152 4.443 2.014E-03 4.369E-02 IRS2 2.154 4.451 6.444E-10 2.125E-07 DUSP2 2.158 4.462 9.808E-15 9.461E-12 MAFB 2.167 4.491 3.263E-07 4.535E-05 ZFP36 2.168 4.493 2.525E-09 7.081E-07 NFKBIA 2.170 4.500 1.211E-11 5.817E-09 NR6A1 2.176 4.518 8.261E-05 4.424E-03 ENSG00000207525 2.182 4.539 6.065E-04 1.906E-02 FOSL2 2.187 4.552 1.416E-11 6.582E-09 AREG 2.189 4.561 5.583E-04 1.789E-02 PPP1R15A 2.196 4.583 8.779E-14 5.905E-11 ICAM1 2.198 4.587 3.686E-12 2.066E-09 SOCS3 2.198 4.587 2.672E-06 2.774E-04 MIR616 2.208 4.619 1.664E-03 3.837E-02 SLC2A3 2.209 4.623 1.570E-18 2.934E-15 PLAU 2.209 4.624 2.676E-05 1.907E-03 DIP2A-IT1 2.209 4.625 4.566E-05 2.865E-03 ENSG00000266993 2.215 4.642 2.278E-03 4.736E-02 PPIF 2.227 4.683 1.967E-12 1.141E-09 NA 2.248 4.749 2.364E-08 4.622E-06 NAMPT 2.259 4.786 4.009E-08 7.328E-06 DUSP6 2.259 4.788 1.487E-07 2.253E-05 ENSG00000256913 2.261 4.793 1.039E-03 2.712E-02 ENSG00000275210 2.272 4.830 9.994E-04 2.651E-02 IFI30 2.282 4.863 9.844E-05 5.044E-03 PIM3 2.285 4.874 1.380E-25 5.800E-22 LGALS12 2.286 4.876 3.171E-05 2.141E-03 ASGR2 2.290 4.890 2.306E-04 9.642E-03 ANPEP 2.291 4.892 1.736E-07 2.606E-05 FFAR1 2.292 4.896 1.448E-11 6.582E-09 CSRNP1 2.299 4.923 5.836E-14 4.267E-11 NFIL3 2.304 4.939 7.050E-08 1.185E-05 TCF3P1 2.307 4.948 9.014E-04 2.473E-02 HLX 2.344 5.077 1.339E-03 3.291E-02 PLK3 2.346 5.085 2.505E-25 8.425E-22 PDE2A 2.351 5.103 2.590E-04 1.047E-02 PFKFB3 2.356 5.121 1.178E-17 1.981E-14 SOWAHC 2.363 5.143 6.411E-04 1.960E-02 TNFRSF12A 2.374 5.183 6.012E-05 3.547E-03 MIR22HG 2.378 5.198 2.038E-09 5.908E-07 XK 2.387 5.230 1.413E-03 3.403E-02 BCL3 2.393 5.254 6.803E-12 3.690E-09 ENSG00000268734 2.402 5.284 3.668E-07 5.015E-05 GADD45G 2.415 5.332 1.857E-03 4.131E-02 ENSG00000274008 2.423 5.363 6.394E-04 1.959E-02 ASTL 2.435 5.409 1.479E-04 6.872E-03 ELOVL7 2.469 5.537 2.200E-03 4.652E-02 MATN1 2.469 5.537 4.546E-04 1.563E-02 TRIB1 2.476 5.562 2.206E-05 1.656E-03 CHRM4 2.507 5.683 7.352E-04 2.154E-02 ENSG00000250138 2.514 5.711 8.650E-05 4.603E-03 ATP2B1-AS1 2.520 5.735 2.634E-05 1.896E-03 PLAUR 2.555 5.875 5.065E-10 1.729E-07 TSPEAR-AS1 2.582 5.989 1.314E-03 3.239E-02 GP9 2.589 6.018 2.218E-03 4.674E-02 AVPI1 2.591 6.023 5.787E-04 1.839E-02 RND1 2.601 6.068 8.633E-04 2.407E-02 PTX3 2.618 6.140 7.139E-12 3.752E-09 NLRP3 2.625 6.168 1.345E-07 2.075E-05 MMP25 2.630 6.191 2.027E-14 1.794E-11 IER3 2.659 6.315 8.094E-13 5.041E-10 FAM238A 2.669 6.359 1.596E-11 6.884E-09 RBKS 2.677 6.395 2.392E-07 3.409E-05 EMP1 2.694 6.471 5.779E-11 2.209E-08 DUSP8 2.700 6.500 2.755E-05 1.938E-03 RRAD 2.718 6.581 5.245E-05 3.207E-03 MIR23AHG 2.733 6.646 6.241E-15 6.559E-12 RAB20 2.739 6.675 8.601E-14 5.905E-11 NA 2.741 6.684 7.517E-17 1.149E-13 MAFF 2.742 6.690 1.013E-14 9.461E-12 TMEM88 2.744 6.700 1.217E-05 1.008E-03 MMP9 2.766 6.802 7.058E-04 2.104E-02 PHLDA1 2.802 6.973 2.759E-07 3.895E-05 CHMP4BP1 2.806 6.992 2.993E-05 2.080E-03 NR4A1 2.843 7.176 2.237E-06 2.396E-04 IGFBP2 2.853 7.226 1.002E-04 5.058E-03 ENSG00000234436 2.893 7.426 5.720E-04 1.825E-02 ENSG00000274677 2.893 7.426 1.663E-04 7.437E-03 PER1 2.898 7.452 1.029E-25 5.765E-22 ENSG00000278022 2.940 7.677 9.969E-05 5.050E-03 ATF3 2.943 7.691 4.281E-11 1.714E-08 NTSR1 2.954 7.747 7.847E-06 7.094E-04 SLC22A16 2.984 7.913 1.026E-03 2.696E-02 TP53INP2 2.990 7.943 1.099E-26 9.240E-23 TMEM119 3.002 8.008 1.083E-03 2.809E-02 CCL2 3.020 8.110 2.218E-04 9.420E-03 THNSL2 3.021 8.116 2.647E-05 1.896E-03 RNVU1-3 3.027 8.148 7.264E-04 2.138E-02 ENSG00000270681 3.038 8.212 7.719E-04 2.219E-02 PANX2 3.042 8.235 6.241E-05 3.645E-03 TAMALIN 3.044 8.249 1.567E-16 2.196E-13 TNFSF9 3.078 8.446 1.045E-11 5.287E-09 NRIP3 3.082 8.467 4.518E-05 2.845E-03 TNF 3.092 8.526 8.842E-10 2.703E-07 MT1XP1 3.114 8.655 1.089E-04 5.419E-03 FCAR 3.125 8.726 8.222E-07 1.032E-04 ENSG00000274051 3.136 8.791 6.113E-04 1.909E-02 PDGFA-DT 3.137 8.797 1.983E-03 4.328E-02 KRT86 3.148 8.866 1.644E-05 1.291E-03 LOC399900 3.149 8.873 3.641E-04 1.328E-02 TREM1 3.164 8.963 7.190E-10 2.325E-07 MIR4420 3.198 9.176 5.616E-14 4.267E-11 ENSG00000224356 3.202 9.202 7.259E-06 6.634E-04 FOSB 3.211 9.260 1.335E-09 4.009E-07 OSM 3.260 9.582 1.623E-08 3.370E-06 C17orf107 3.312 9.931 8.022E-05 4.324E-03 HP 3.333 10.078 9.749E-04 2.615E-02 RNU5D-1 3.342 10.140 1.076E-03 2.797E-02 CD83 3.385 10.448 1.852E-33 3.114E-29 CXCL2 3.402 10.573 1.213E-06 1.427E-04 HBEGF 3.505 11.350 1.069E-11 5.287E-09 SGK1 3.516 11.443 1.492E-11 6.602E-09 B3GNT5 3.536 11.600 7.350E-07 9.363E-05 NR4A3 3.586 12.011 1.649E-11 6.932E-09 NR4A2 3.622 12.313 6.717E-23 1.883E-19 FAM71A 3.657 12.618 5.086E-04 1.680E-02 ZNF503 3.707 13.055 6.415E-09 1.659E-06 LRRC32 3.721 13.190 7.182E-09 1.773E-06 ENSG00000280407 3.756 13.514 2.566E-05 1.860E-03 GJB6 3.764 13.585 2.250E-04 9.505E-03 PHLDA2 3.834 14.263 5.363E-07 7.069E-05 THBS1 3.897 14.896 2.312E-03 4.767E-02 IL1B 3.901 14.942 2.202E-15 2.645E-12 SEMA6B 3.922 15.161 1.147E-04 5.658E-03 RNVU1-6 3.981 15.794 1.348E-04 6.387E-03 RNF152 4.010 16.115 2.091E-03 4.490E-02 SPX 4.028 16.315 1.538E-03 3.597E-02 SNORD3B-2 4.092 17.048 2.855E-04 1.124E-02 ENSG00000218809 4.104 17.192 1.987E-08 3.966E-06 RN7SL368P 4.609 24.404 7.879E-05 4.282E-03 TEX45 4.751 26.919 6.112E-04 1.909E-02 CCL3L3 4.768 27.241 5.399E-04 1.756E-02 EGR1 4.840 28.632 2.278E-04 9.579E-03 G0S2 4.981 31.578 5.628E-20 1.352E-16 CXCL8 4.995 31.887 9.194E-05 4.801E-03 EGR3 5.076 33.732 4.196E-04 1.470E-02 ADRA2B 5.110 34.527 2.412E-04 9.943E-03 LINC01220 5.216 37.168 6.991E-05 3.955E-03 SLED1 5.246 37.958 1.372E-06 1.603E-04 ID1 5.485 44.786 4.129E-09 1.138E-06 ENSG00000224029 5.501 45.302 4.341E-04 1.508E-02 EGR2 5.788 55.266 3.139E-05 2.137E-03 MMP2-AS1 6.120 69.545 1.158E-03 2.943E-02 ENSG00000258413 6.192 73.113 1.445E-03 3.448E-02 FOSL1 6.357 81.941 7.520E-19 1.581E-15 CXCL1 6.439 86.742 7.316E-04 2.147E-02 LERFS 6.597 96.823 4.893E-04 1.652E-02 ENSG00000261026 6.791 110.769 6.213E-05 3.645E-03 CLLU1-AS1 8.387 334.831 1.475E-09 4.350E-07 AD aged >6 mo (n = 5) versus AD aged <6 mo (n = 3) WASHC1 ‒2.328 0.199 3.255E-10 5.279E-06 MYO18B ‒4.947 0.032 2.603E-06 1.477E-02 IFI27 ‒3.795 0.072 2.732E-06 1.477E-02 NRIR ‒2.206 0.217 8.777E-06 3.558E-02 HCs aged >6 mo (n = 2) versus HCs aged <6 mo (n = 3) ENSG00000213058 ‒7.336 0.006 8.210E-06 3.863E-04 RPS14P1 ‒6.971 0.008 4.300E-05 1.468E-03 RPL23P3 ‒6.413 0.012 5.931E-04 1.061E-02 CLEC4F ‒5.654 0.020 2.039E-03 2.629E-02 FCGR3B ‒4.753 0.037 4.584E-03 4.626E-02 IFIT3 ‒4.526 0.043 6.902E-04 1.182E-02 AGAP14P ‒4.423 0.047 2.570E-05 9.886E-04 NAALAD2 ‒4.269 0.052 3.906E-03 4.164E-02 IFIT1 ‒4.029 0.061 3.432E-03 3.804E-02 P2RY12 ‒4.015 0.062 4.380E-04 8.525E-03 ENSG00000254851 ‒3.978 0.063 2.595E-03 3.152E-02 EFHB ‒3.961 0.064 1.762E-03 2.363E-02 PFN1P1 ‒3.950 0.065 3.605E-03 3.958E-02 CXCL10 ‒3.923 0.066 3.740E-07 2.960E-05 L1TD1 ‒3.846 0.070 3.650E-08 3.750E-06 FPR2 ‒3.678 0.078 4.660E-13 1.850E-10 GPR20 ‒3.606 0.082 5.070E-03 4.963E-02 LINC02432 ‒3.506 0.088 8.400E-07 5.800E-05 ENSG00000276758 ‒3.502 0.088 2.538E-03 3.100E-02 ANKRD22 ‒3.458 0.091 6.360E-06 3.128E-04 ZBED2 ‒3.352 0.098 2.091E-04 5.014E-03 P2RY13 ‒3.293 0.102 2.920E-10 5.790E-08 PPP1R17 ‒3.272 0.104 1.290E-08 1.500E-06 NAGS ‒3.192 0.109 2.293E-03 2.863E-02 FAM20A ‒3.164 0.112 2.420E-07 2.090E-05 FILIP1L ‒3.149 0.113 5.340E-04 9.756E-03 ASH2LP1 ‒3.135 0.114 4.320E-08 4.420E-06 LINC01506 ‒3.090 0.117 1.024E-03 1.591E-02 CCDC121 ‒3.043 0.121 1.007E-03 1.572E-02 NDN ‒2.991 0.126 1.018E-03 1.585E-02 CX3CR1 ‒2.971 0.128 1.589E-04 4.006E-03 SCARA5 ‒2.957 0.129 9.880E-04 1.550E-02 GPR82 ‒2.940 0.130 3.116E-03 3.563E-02 RAVER2 ‒2.931 0.131 4.369E-03 4.490E-02 C3AR1 ‒2.920 0.132 7.920E-12 2.400E-09 SFTPD ‒2.851 0.139 1.863E-03 2.459E-02 GATA2 ‒2.842 0.139 4.630E-04 8.797E-03 CYP4F22 ‒2.805 0.143 1.490E-06 9.340E-05 PTGDR2 ‒2.782 0.145 3.070E-14 1.600E-11 NA ‒2.742 0.149 2.330E-07 2.020E-05 OLFML2B ‒2.707 0.153 2.643E-03 3.192E-02 OAS1 ‒2.704 0.153 9.279E-04 1.478E-02 CXCR1 ‒2.653 0.159 2.508E-04 5.733E-03 TLR8 ‒2.651 0.159 1.510E-09 2.310E-07 NLRC4 ‒2.642 0.160 3.610E-06 2.014E-04 CCR2 ‒2.640 0.160 9.070E-13 3.360E-10 S1PR3 ‒2.621 0.163 2.945E-03 3.436E-02 CD180 ‒2.618 0.163 5.740E-18 5.030E-15 ENSG00000261655 ‒2.597 0.165 1.793E-04 4.432E-03 RET ‒2.594 0.166 6.200E-05 1.931E-03 TMEM51 ‒2.583 0.167 3.675E-03 4.002E-02 HGF ‒2.582 0.167 6.970E-05 2.100E-03 IGSF6 ‒2.544 0.171 3.770E-07 2.960E-05 XAF1 ‒2.542 0.172 4.601E-03 4.632E-02 ENSG00000244167 ‒2.540 0.172 5.150E-05 1.696E-03 CISH ‒2.536 0.172 7.870E-16 4.860E-13 SIGLEC5 ‒2.509 0.176 2.174E-04 5.166E-03 C3 ‒2.503 0.176 5.271E-04 9.661E-03 MOCS2-DT ‒2.497 0.177 2.500E-06 1.454E-04 TNFSF10 ‒2.480 0.179 3.380E-20 4.340E-17 CEACAM3 ‒2.413 0.188 5.356E-04 9.773E-03 AATBC ‒2.413 0.188 2.713E-03 3.243E-02 KCNE3 ‒2.388 0.191 1.140E-05 5.160E-04 PRICKLE1 ‒2.382 0.192 8.130E-07 5.640E-05 HSPA1A ‒2.329 0.199 2.020E-11 5.360E-09 HECW2 ‒2.328 0.199 3.273E-03 3.677E-02 PDK4 ‒2.317 0.201 2.060E-10 4.460E-08 DAZL ‒2.287 0.205 3.266E-03 3.675E-02 CDKN1C ‒2.230 0.213 2.010E-19 2.230E-16 CARD6 ‒2.187 0.220 2.910E-11 7.450E-09 ICAM4 ‒2.168 0.222 2.367E-04 5.508E-03 MYOF ‒2.148 0.226 3.050E-06 1.735E-04 FPR1 ‒2.123 0.230 2.210E-26 5.830E-23 FGL2 ‒2.122 0.230 3.672E-03 4.001E-02 LILRA6 ‒2.119 0.230 1.780E-05 7.353E-04 TLR10 ‒2.117 0.231 2.050E-11 5.360E-09 CCR1 ‒2.092 0.235 2.990E-08 3.170E-06 RGS18 ‒2.089 0.235 4.505E-04 8.648E-03 CXCR2 ‒2.082 0.236 3.500E-05 1.250E-03 GTF2H2 ‒2.073 0.238 1.280E-07 1.210E-05 FZD1 ‒2.061 0.240 4.600E-05 1.547E-03 BATF2 ‒2.057 0.240 3.069E-03 3.531E-02 SOWAHD ‒2.056 0.241 1.090E-06 7.290E-05 IRAG1 ‒2.052 0.241 4.760E-07 3.590E-05 MIR5195 ‒2.035 0.244 6.010E-06 2.991E-04 CDC42EP2 ‒2.033 0.244 5.500E-05 1.775E-03 ENSG00000227615 ‒2.030 0.245 6.680E-10 1.140E-07 GPBAR1 ‒2.010 0.248 4.630E-09 6.270E-07 OAS2 ‒2.009 0.248 4.692E-03 4.699E-02 LINC01504 ‒1.998 0.250 6.430E-05 1.983E-03 LRRC25 ‒1.991 0.252 1.420E-08 1.630E-06 SLC31A2 ‒1.987 0.252 3.510E-07 2.810E-05 SENCR ‒1.986 0.252 3.747E-03 4.041E-02 PELATON ‒1.984 0.253 1.100E-11 3.110E-09 GAPT ‒1.978 0.254 2.060E-11 5.360E-09 IGHV5-78 ‒1.977 0.254 1.280E-08 1.500E-06 TMEM60 ‒1.973 0.255 1.690E-09 2.550E-07 ROR1 ‒1.962 0.257 3.031E-03 3.500E-02 TLR7 ‒1.961 0.257 2.450E-08 2.670E-06 FFAR2 ‒1.938 0.261 9.490E-05 2.687E-03 HSPA6 ‒1.938 0.261 3.690E-04 7.515E-03 FCGR3A ‒1.937 0.261 1.270E-13 5.880E-11 NFE2 ‒1.908 0.266 1.430E-08 1.640E-06 FNDC5 ‒1.900 0.268 1.033E-04 2.882E-03 SAMD9L ‒1.876 0.273 1.471E-03 2.076E-02 GEMIN6 ‒1.873 0.273 5.100E-07 3.780E-05 FMNL2 ‒1.871 0.273 1.701E-04 4.248E-03 IGLV3-27 ‒1.864 0.275 1.210E-05 5.409E-04 PRSS30P ‒1.864 0.275 1.497E-03 2.106E-02 MS4A7 ‒1.862 0.275 3.310E-08 3.460E-06 GIMAP4 ‒1.853 0.277 1.070E-26 3.560E-23 SAMD9 ‒1.848 0.278 4.260E-10 7.880E-08 FZD2 ‒1.845 0.278 3.042E-03 3.507E-02 ISL2 ‒1.841 0.279 4.605E-03 4.633E-02 LINC02576 ‒1.838 0.280 3.872E-03 4.140E-02 ENSG00000257275 ‒1.817 0.284 4.550E-07 3.460E-05 ERAP2 ‒1.808 0.286 7.980E-32 6.650E-28 CCDC126 ‒1.803 0.287 3.840E-05 1.343E-03 TASL ‒1.801 0.287 3.530E-14 1.780E-11 SOS1-IT1 ‒1.799 0.287 5.103E-04 9.447E-03 AQP9 ‒1.797 0.288 3.120E-05 1.147E-03 LOC105377623 ‒1.790 0.289 2.519E-03 3.082E-02 UGGT2 ‒1.754 0.296 1.282E-03 1.885E-02 CD24 ‒1.748 0.298 8.600E-09 1.090E-06 FKBPL ‒1.747 0.298 1.998E-04 4.838E-03 PLA2G2D ‒1.745 0.298 1.614E-03 2.228E-02 OLIG1 ‒1.737 0.300 9.447E-04 1.503E-02 KLK1 ‒1.735 0.300 4.544E-03 4.608E-02 TCL1A ‒1.731 0.301 3.480E-10 6.590E-08 PARS2 ‒1.729 0.302 7.571E-04 1.266E-02 ENSG00000261222 ‒1.720 0.303 5.548E-04 1.010E-02 MTMR11 ‒1.714 0.305 2.341E-04 5.470E-03 CALHM2 ‒1.713 0.305 1.930E-09 2.870E-07 MIR223HG ‒1.712 0.305 8.440E-14 4.020E-11 MSR1 ‒1.710 0.306 4.511E-03 4.591E-02 ENSG00000279696 ‒1.702 0.307 4.450E-06 2.370E-04 MGC16275 ‒1.696 0.309 1.449E-03 2.056E-02 SMCO4 ‒1.677 0.313 1.040E-06 6.980E-05 GCNT1 ‒1.664 0.315 1.510E-13 6.640E-11 GUCY1B1 ‒1.657 0.317 2.921E-03 3.417E-02 SPTA1 ‒1.648 0.319 5.100E-03 4.983E-02 CEBPA ‒1.638 0.321 1.121E-04 3.076E-03 LINC01355 ‒1.635 0.322 2.380E-10 4.970E-08 CKB ‒1.632 0.323 5.940E-05 1.885E-03 SLAMF8 ‒1.618 0.326 1.039E-03 1.606E-02 LPCAT2 ‒1.614 0.327 2.918E-03 3.417E-02 HS3ST1 ‒1.594 0.331 1.160E-07 1.110E-05 C9orf64 ‒1.583 0.334 5.090E-06 2.633E-04 C1orf220 ‒1.583 0.334 8.730E-06 4.051E-04 TRIM69 ‒1.581 0.334 6.100E-07 4.400E-05 B3GNT8 ‒1.580 0.334 2.682E-03 3.222E-02 KCNQ1OT1 ‒1.575 0.336 1.056E-04 2.932E-03 DTX3L ‒1.568 0.337 1.530E-05 6.538E-04 FCRLB ‒1.566 0.338 1.747E-03 2.346E-02 SECTM1 ‒1.563 0.339 6.220E-05 1.935E-03 LMO2 ‒1.553 0.341 6.500E-05 1.997E-03 C14orf119 ‒1.553 0.341 1.010E-15 6.010E-13 ENSG00000279611 ‒1.546 0.343 4.701E-03 4.702E-02 HMOX1 ‒1.543 0.343 1.680E-05 7.022E-04 ADPRH ‒1.538 0.344 8.100E-06 3.835E-04 MIR4645 ‒1.537 0.345 2.188E-03 2.774E-02 ATP9A ‒1.537 0.345 9.535E-04 1.514E-02 TNFAIP8L2 ‒1.533 0.346 1.380E-13 6.210E-11 TNFRSF8 ‒1.532 0.346 5.600E-07 4.090E-05 CD101 ‒1.532 0.346 1.404E-03 2.012E-02 LOC100287896 ‒1.532 0.346 3.405E-03 3.785E-02 MAFB ‒1.528 0.347 2.330E-07 2.020E-05 IGHJ3 ‒1.527 0.347 4.816E-03 4.776E-02 DUSP6 ‒1.524 0.348 2.180E-09 3.180E-07 ZNF404 ‒1.523 0.348 6.190E-05 1.930E-03 HECW2-AS1 ‒1.521 0.348 4.760E-05 1.584E-03 CCR5 ‒1.521 0.348 4.240E-07 3.270E-05 RTP4 ‒1.518 0.349 6.874E-04 1.179E-02 ZNF594 ‒1.514 0.350 1.640E-08 1.850E-06 LINC00324 ‒1.511 0.351 9.090E-07 6.230E-05 ZNF2 ‒1.507 0.352 3.583E-04 7.393E-03 CPM ‒1.504 0.353 2.150E-04 5.116E-03 LILRB3 ‒1.502 0.353 7.820E-06 3.756E-04 LACTB2 ‒1.501 0.353 1.611E-04 4.048E-03 TREML2 ‒1.488 0.357 3.180E-07 2.580E-05 HYAL2 ‒1.475 0.360 8.192E-04 1.342E-02 ABCC3 ‒1.473 0.360 1.356E-03 1.967E-02 APOBEC3A ‒1.471 0.361 9.350E-05 2.667E-03 SLC37A2 ‒1.456 0.364 4.837E-04 9.086E-03 FASLG ‒1.456 0.365 5.238E-04 9.622E-03 C2orf74-DT ‒1.454 0.365 7.110E-04 1.209E-02 SIGLEC9 ‒1.452 0.365 6.010E-04 1.072E-02 METTL7A ‒1.451 0.366 4.190E-09 5.770E-07 MERTK ‒1.440 0.368 5.084E-04 9.422E-03 MPEG1 ‒1.436 0.370 2.350E-06 1.372E-04 ZNF772 ‒1.432 0.371 2.930E-08 3.130E-06 ENSG00000213976 ‒1.432 0.371 2.061E-04 4.963E-03 EEF1AKNMT ‒1.431 0.371 1.190E-12 4.200E-10 FANCL ‒1.431 0.371 1.368E-03 1.974E-02 PTPN13 ‒1.429 0.371 1.868E-03 2.465E-02 CARD8-AS1 ‒1.423 0.373 9.660E-08 9.580E-06 EOMES ‒1.417 0.374 2.810E-05 1.047E-03 ARHGEF2-AS2 ‒1.417 0.375 8.446E-04 1.370E-02 RIN2 ‒1.410 0.376 6.321E-04 1.113E-02 DOK1 ‒1.409 0.376 7.160E-10 1.200E-07 RPP40 ‒1.408 0.377 9.037E-04 1.444E-02 IKBIP ‒1.406 0.377 9.800E-05 2.758E-03 PPIL1 ‒1.403 0.378 1.960E-06 1.186E-04 IL12RB2 ‒1.401 0.379 3.335E-03 3.732E-02 ZNF28 ‒1.395 0.380 2.710E-10 5.540E-08 CALHM6 ‒1.394 0.381 2.730E-06 1.585E-04 BATF3 ‒1.392 0.381 9.785E-04 1.544E-02 PLEKHO2 ‒1.387 0.382 3.450E-05 1.240E-03 CFD ‒1.386 0.383 1.290E-05 5.688E-04 PAQR8 ‒1.378 0.385 1.370E-15 7.600E-13 LYL1 ‒1.377 0.385 3.210E-09 4.490E-07 MME ‒1.375 0.385 1.296E-04 3.434E-03 ACKR3 ‒1.374 0.386 2.048E-03 2.637E-02 ERI2 ‒1.373 0.386 3.010E-03 3.486E-02 MIR3142HG ‒1.372 0.386 1.712E-03 2.314E-02 LOC100507642 ‒1.370 0.387 7.370E-04 1.244E-02 PHF23 ‒1.358 0.390 9.300E-13 3.370E-10 SLC1A5 ‒1.354 0.391 1.930E-07 1.740E-05 FCGR2A ‒1.350 0.392 2.890E-03 3.394E-02 TOR4A ‒1.347 0.393 5.020E-07 3.740E-05 GBP1 ‒1.347 0.393 7.940E-07 5.560E-05 TRMT5 ‒1.336 0.396 3.285E-04 6.876E-03 ZNF583 ‒1.334 0.397 7.960E-06 3.809E-04 HSD17B7P2 ‒1.331 0.397 1.180E-06 7.710E-05 NEURL1 ‒1.331 0.397 2.470E-07 2.110E-05 TMEM187 ‒1.331 0.398 4.428E-04 8.558E-03 IRAK3 ‒1.329 0.398 1.075E-03 1.652E-02 FCRLA ‒1.323 0.400 1.210E-05 5.393E-04 UBE2T ‒1.321 0.400 1.458E-03 2.065E-02 PCTP ‒1.315 0.402 5.240E-05 1.724E-03 PLP2 ‒1.314 0.402 9.830E-04 1.544E-02 LILRA2 ‒1.314 0.402 2.914E-03 3.416E-02 FAM111A-DT ‒1.309 0.404 2.550E-05 9.866E-04 SCIMP ‒1.304 0.405 4.207E-04 8.286E-03 HOMEZ ‒1.295 0.408 1.380E-07 1.290E-05 CEP19 ‒1.295 0.408 2.026E-03 2.618E-02 ZNF613 ‒1.289 0.409 3.699E-04 7.515E-03 LPAR6 ‒1.288 0.410 1.960E-09 2.890E-07 SRD5A3 ‒1.288 0.410 7.341E-04 1.240E-02 SLAMF7 ‒1.286 0.410 1.300E-05 5.718E-04 ZNF626 ‒1.284 0.411 1.163E-03 1.753E-02 DNASE1L3 ‒1.283 0.411 3.735E-03 4.040E-02 STAT2 ‒1.263 0.417 2.690E-05 1.015E-03 TBC1D8 ‒1.261 0.417 4.760E-05 1.584E-03 CPPED1 ‒1.260 0.418 2.761E-03 3.279E-02 ASCL2 ‒1.254 0.419 1.172E-04 3.191E-03 LBH ‒1.253 0.420 3.350E-11 8.220E-09 CENPBD1 ‒1.251 0.420 1.053E-03 1.624E-02 ANKRD50 ‒1.250 0.420 2.015E-03 2.610E-02 SLFN12 ‒1.243 0.423 2.490E-07 2.110E-05 ZNF181 ‒1.238 0.424 3.000E-05 1.115E-03 STAT1 ‒1.237 0.424 2.053E-04 4.963E-03 CLEC4C ‒1.236 0.424 8.864E-04 1.424E-02 S100A11 ‒1.235 0.425 2.330E-05 9.237E-04 UGDH ‒1.232 0.426 2.366E-03 2.935E-02 TMEM102 ‒1.231 0.426 1.510E-05 6.490E-04 TNFSF13B ‒1.229 0.426 4.534E-03 4.603E-02 NA ‒1.229 0.427 3.618E-04 7.403E-03 KIAA0040 ‒1.223 0.428 3.210E-07 2.600E-05 MKKS ‒1.221 0.429 1.460E-07 1.350E-05 IL18 ‒1.219 0.430 4.469E-03 4.562E-02 C5AR2 ‒1.218 0.430 1.241E-03 1.833E-02 IGHV1-46 ‒1.215 0.431 3.240E-05 1.176E-03 ARL11 ‒1.214 0.431 4.450E-04 8.582E-03 INTS5 ‒1.211 0.432 1.080E-07 1.050E-05 FCF1P2 ‒1.210 0.432 1.403E-03 2.012E-02 APOBEC3G ‒1.207 0.433 2.488E-04 5.708E-03 ZNNT1 ‒1.206 0.433 5.280E-05 1.725E-03 RMI2 ‒1.202 0.435 1.260E-03 1.855E-02 WDCP ‒1.201 0.435 6.150E-06 3.038E-04 TNFSF13 ‒1.201 0.435 2.655E-03 3.196E-02 DUSP18 ‒1.200 0.435 5.990E-05 1.895E-03 HCK ‒1.199 0.435 4.173E-04 8.248E-03 PILRA ‒1.198 0.436 2.697E-03 3.232E-02 BBS10 ‒1.198 0.436 1.015E-04 2.848E-03 ATP6AP1L ‒1.198 0.436 1.217E-03 1.813E-02 HSD17B1-AS1 ‒1.196 0.436 1.510E-07 1.390E-05 POLR1G ‒1.196 0.436 1.774E-03 2.370E-02 LRRN3 ‒1.195 0.437 3.750E-05 1.317E-03 USP27X ‒1.192 0.438 2.640E-04 5.947E-03 LOC101927151 ‒1.191 0.438 1.292E-04 3.433E-03 TNFRSF1A ‒1.188 0.439 5.630E-07 4.090E-05 DDX60 ‒1.185 0.440 3.927E-03 4.173E-02 TOB2 ‒1.183 0.440 3.710E-07 2.950E-05 PECAM1 ‒1.183 0.440 5.970E-10 1.030E-07 PNP ‒1.183 0.441 5.320E-06 2.736E-04 RNASEL ‒1.182 0.441 2.120E-12 6.910E-10 C1orf162 ‒1.180 0.441 4.700E-10 8.410E-08 ADAMTSL4 ‒1.180 0.441 7.991E-04 1.318E-02 BTN3A2 ‒1.180 0.441 2.363E-04 5.506E-03 GIMAP1 ‒1.178 0.442 1.960E-10 4.290E-08 JRKL ‒1.176 0.443 4.600E-05 1.547E-03 IL1RN ‒1.175 0.443 9.194E-04 1.466E-02 ZNF285 ‒1.174 0.443 2.190E-05 8.742E-04 TPPP3 ‒1.174 0.443 9.537E-04 1.514E-02 RNASE6 ‒1.173 0.443 2.160E-14 1.160E-11 ENSG00000272335 ‒1.173 0.443 2.948E-03 3.437E-02 LAP3 ‒1.173 0.444 8.283E-04 1.349E-02 CD86 ‒1.172 0.444 5.029E-04 9.348E-03 CASP1 ‒1.172 0.444 3.550E-06 1.983E-04 LTBR ‒1.170 0.445 2.660E-03 3.200E-02 ADAP2 ‒1.168 0.445 3.579E-04 7.393E-03 KLRD1 ‒1.162 0.447 1.602E-03 2.224E-02 VMP1 ‒1.160 0.447 7.660E-05 2.259E-03 PLEK ‒1.149 0.451 1.570E-06 9.790E-05 TRAFD1 ‒1.144 0.453 6.480E-07 4.630E-05 ABI3 ‒1.144 0.453 1.180E-06 7.710E-05 HAL ‒1.141 0.453 2.249E-03 2.830E-02 KCTD21 ‒1.137 0.455 1.600E-05 6.781E-04 ENSG00000256448 ‒1.137 0.455 1.332E-03 1.940E-02 CYBB ‒1.135 0.455 3.195E-04 6.754E-03 ENSG00000260285 ‒1.133 0.456 1.768E-03 2.368E-02 FAM241A ‒1.132 0.456 5.080E-04 9.422E-03 NMI ‒1.131 0.457 2.150E-06 1.273E-04 SLC45A3 ‒1.129 0.457 3.666E-03 3.999E-02 PPP1R18 ‒1.127 0.458 5.600E-06 2.835E-04 HCG11 ‒1.127 0.458 2.639E-04 5.947E-03 GIMAP8 ‒1.124 0.459 3.390E-10 6.580E-08 FCRL5 ‒1.124 0.459 6.368E-04 1.118E-02 FGD2 ‒1.123 0.459 5.260E-05 1.724E-03 PTPRO ‒1.123 0.459 1.100E-08 1.330E-06 PGBD2 ‒1.122 0.460 1.100E-07 1.060E-05 TPTEP1 ‒1.120 0.460 4.080E-05 1.408E-03 UTP14C ‒1.116 0.461 4.080E-06 2.210E-04 INIP ‒1.115 0.462 2.610E-05 1.000E-03 UBE2L6 ‒1.113 0.462 2.381E-03 2.943E-02 BTLA ‒1.111 0.463 9.090E-06 4.206E-04 APOBEC3C ‒1.109 0.464 3.420E-10 6.580E-08 ZKSCAN7 ‒1.108 0.464 4.324E-04 8.457E-03 RCBTB2 ‒1.108 0.464 1.027E-03 1.591E-02 ZNF470 ‒1.106 0.465 2.219E-04 5.237E-03 ZNF681 ‒1.105 0.465 7.397E-04 1.247E-02 CD79B ‒1.105 0.465 5.150E-06 2.657E-04 ENSG00000224376 ‒1.103 0.465 3.860E-03 4.136E-02 FLVCR1-DT ‒1.103 0.466 2.981E-03 3.461E-02 KLRK1 ‒1.102 0.466 2.644E-03 3.192E-02 RASSF4 ‒1.102 0.466 1.567E-04 3.985E-03 CTSS ‒1.102 0.466 4.441E-03 4.547E-02 DHFR2 ‒1.100 0.467 8.841E-04 1.422E-02 SPN ‒1.100 0.467 1.170E-06 7.680E-05 RALB ‒1.099 0.467 1.720E-05 7.147E-04 UICLM ‒1.098 0.467 7.470E-05 2.216E-03 LRIF1 ‒1.096 0.468 4.036E-04 8.043E-03 GLRX ‒1.095 0.468 1.990E-07 1.780E-05 TUBB6 ‒1.095 0.468 1.079E-04 2.991E-03 SLC29A1 ‒1.095 0.468 6.040E-05 1.898E-03 CD200 ‒1.094 0.469 1.800E-06 1.105E-04 FCER1G ‒1.091 0.469 1.248E-03 1.840E-02 IRF5 ‒1.089 0.470 8.010E-04 1.320E-02 GNS ‒1.087 0.471 2.959E-03 3.441E-02 TCF7L2 ‒1.084 0.472 6.690E-06 3.258E-04 ZNF189 ‒1.084 0.472 1.020E-07 1.010E-05 CMTR2 ‒1.084 0.472 1.730E-11 4.720E-09 FAM214B ‒1.083 0.472 3.420E-08 3.560E-06 MARCKS ‒1.082 0.472 4.835E-03 4.787E-02 GIMAP7 ‒1.082 0.473 6.790E-05 2.063E-03 LINC01013 ‒1.081 0.473 2.989E-04 6.441E-03 PUS3 ‒1.078 0.474 2.080E-05 8.385E-04 SLC15A2 ‒1.078 0.474 2.390E-05 9.377E-04 GCSAM ‒1.075 0.475 8.230E-09 1.050E-06 TRGC2 ‒1.074 0.475 3.750E-10 7.020E-08 FAM110A ‒1.074 0.475 7.300E-10 1.210E-07 LACTB ‒1.072 0.476 2.431E-04 5.617E-03 GPATCH11 ‒1.070 0.476 8.420E-07 5.800E-05 WARS1 ‒1.069 0.477 1.080E-11 3.090E-09 DYNLL1 ‒1.068 0.477 2.960E-06 1.686E-04 CHRNB1 ‒1.068 0.477 2.403E-04 5.577E-03 FCRL3 ‒1.067 0.477 2.550E-07 2.150E-05 ATP6V1D ‒1.066 0.478 1.420E-06 8.930E-05 CETN3 ‒1.064 0.478 3.247E-04 6.821E-03 MRPL18 ‒1.061 0.479 2.270E-07 2.000E-05 TMEM223 ‒1.059 0.480 7.130E-06 3.462E-04 PYGO2 ‒1.059 0.480 1.300E-08 1.500E-06 KYNU ‒1.057 0.481 3.775E-03 4.063E-02 PLSCR1 ‒1.055 0.481 4.601E-03 4.632E-02 C5AR1 ‒1.053 0.482 2.546E-03 3.105E-02 LST1 ‒1.053 0.482 3.431E-04 7.127E-03 RNF144B ‒1.051 0.483 1.890E-05 7.709E-04 FAM220A ‒1.045 0.485 2.789E-04 6.162E-03 RIN1 ‒1.043 0.485 1.947E-03 2.540E-02 CRTAM ‒1.041 0.486 1.554E-03 2.168E-02 EVI2B ‒1.040 0.486 3.140E-05 1.148E-03 LILRB1 ‒1.039 0.487 1.270E-05 5.627E-04 RAB10 ‒1.038 0.487 5.030E-07 3.740E-05 IL3RA ‒1.037 0.487 1.840E-03 2.437E-02 FCGR2B ‒1.035 0.488 4.392E-04 8.539E-03 DCLRE1B ‒1.033 0.489 1.202E-03 1.800E-02 SPIB ‒1.033 0.489 3.184E-03 3.606E-02 ZNF429 ‒1.033 0.489 2.480E-04 5.700E-03 OPA3 ‒1.031 0.489 7.460E-05 2.215E-03 GPR171 ‒1.029 0.490 2.780E-06 1.602E-04 CDC42EP3 ‒1.029 0.490 4.700E-03 4.702E-02 SIGLEC10 ‒1.029 0.490 2.730E-10 5.540E-08 TIGD7 ‒1.026 0.491 2.080E-05 8.376E-04 RNF122 ‒1.024 0.492 6.710E-07 4.760E-05 SLC7A7 ‒1.024 0.492 2.823E-03 3.322E-02 KIAA0930 ‒1.023 0.492 1.210E-12 4.200E-10 ERLIN1 ‒1.021 0.493 4.880E-06 2.555E-04 RUNDC1 ‒1.021 0.493 1.790E-05 7.398E-04 ZNF616 ‒1.019 0.493 8.790E-05 2.521E-03 LINC02397 ‒1.019 0.494 2.840E-06 1.630E-04 FASTKD1 ‒1.019 0.494 1.100E-07 1.060E-05 MED11 ‒1.019 0.494 5.590E-07 4.090E-05 VPREB3 ‒1.017 0.494 1.564E-03 2.180E-02 WSB1 ‒1.016 0.494 1.170E-07 1.120E-05 SMIM14 ‒1.015 0.495 1.700E-06 1.049E-04 LOC101929698 ‒1.012 0.496 2.827E-04 6.213E-03 SAMD4A ‒1.011 0.496 6.553E-04 1.142E-02 KEAP1 ‒1.009 0.497 5.880E-05 1.873E-03 MRPL35 ‒1.007 0.498 6.320E-05 1.958E-03 DHRS4-AS1 ‒1.006 0.498 1.310E-05 5.726E-04 NAGA ‒1.006 0.498 7.165E-04 1.217E-02 TMEM69 ‒1.004 0.499 8.350E-06 3.911E-04 MED20 ‒1.002 0.499 9.210E-06 4.249E-04 ZNF747-DT ‒1.000 0.500 2.951E-03 3.438E-02 NAPSB ‒0.996 0.501 6.440E-05 1.983E-03 FAM200A ‒0.996 0.501 9.017E-04 1.444E-02 SLFN11 ‒0.994 0.502 8.150E-11 1.860E-08 SAC3D1 ‒0.993 0.502 8.717E-04 1.405E-02 GBGT1 ‒0.993 0.502 2.652E-04 5.947E-03 HERPUD2-AS1 ‒0.992 0.503 1.313E-04 3.467E-03 DAPP1 ‒0.991 0.503 6.790E-11 1.620E-08 TRDC ‒0.991 0.503 5.847E-04 1.052E-02 THNSL1 ‒0.988 0.504 2.648E-03 3.192E-02 IFI16 ‒0.986 0.505 9.310E-06 4.287E-04 POU2F2-AS1 ‒0.985 0.505 4.342E-03 4.469E-02 LILRA5 ‒0.984 0.506 4.738E-03 4.716E-02 LILRB2 ‒0.977 0.508 3.090E-03 3.548E-02 LAT2 ‒0.974 0.509 5.718E-04 1.033E-02 ALDH6A1 ‒0.974 0.509 3.542E-03 3.898E-02 SLC43A3 ‒0.974 0.509 6.830E-05 2.074E-03 AIF1 ‒0.971 0.510 2.695E-03 3.232E-02 YWHAH ‒0.968 0.511 6.491E-04 1.134E-02 MPZL1 ‒0.967 0.512 5.960E-05 1.888E-03 HCP5 ‒0.965 0.512 1.300E-07 1.230E-05 PRCP ‒0.964 0.513 4.170E-05 1.428E-03 CD300LB ‒0.963 0.513 2.151E-03 2.744E-02 C6orf47 ‒0.962 0.513 1.250E-05 5.549E-04 LPAR5 ‒0.961 0.514 7.540E-05 2.228E-03 GLIPR1 ‒0.959 0.514 1.412E-04 3.652E-03 TTC9C ‒0.958 0.515 2.160E-05 8.654E-04 ARV1 ‒0.958 0.515 2.602E-04 5.899E-03 SELPLG ‒0.958 0.515 3.480E-06 1.960E-04 LINC00847 ‒0.956 0.516 2.380E-05 9.366E-04 QRSL1 ‒0.955 0.516 1.520E-10 3.370E-08 NCF1 ‒0.953 0.516 2.739E-04 6.060E-03 RRAS ‒0.946 0.519 2.787E-03 3.295E-02 TIGD2 ‒0.945 0.519 4.460E-04 8.591E-03 CYSLTR1 ‒0.943 0.520 1.079E-03 1.656E-02 TNFRSF1B ‒0.941 0.521 5.580E-05 1.799E-03 IGLV2-14 ‒0.939 0.521 6.289E-04 1.109E-02 MCM8 ‒0.938 0.522 6.061E-04 1.079E-02 WEE1 ‒0.938 0.522 4.960E-05 1.641E-03 BORCS6 ‒0.938 0.522 3.530E-05 1.258E-03 GNB4 ‒0.937 0.522 1.619E-03 2.231E-02 HNRNPF ‒0.936 0.523 2.560E-08 2.770E-06 PWWP2B ‒0.936 0.523 3.854E-03 4.133E-02 BTK ‒0.935 0.523 8.560E-05 2.467E-03 CD1C ‒0.934 0.523 6.590E-05 2.021E-03 NCOA4 ‒0.933 0.524 8.071E-04 1.328E-02 POLH ‒0.932 0.524 2.100E-04 5.021E-03 SKAP2 ‒0.932 0.524 1.219E-03 1.814E-02 ENSG00000246596 ‒0.932 0.524 1.175E-03 1.768E-02 RXRA ‒0.931 0.524 2.741E-03 3.266E-02 ZDHHC7 ‒0.929 0.525 3.696E-04 7.515E-03 LAX1 ‒0.929 0.525 2.646E-04 5.947E-03 SDHAF1 ‒0.927 0.526 1.095E-03 1.674E-02 IFITM2 ‒0.927 0.526 3.236E-03 3.655E-02 SLC40A1 ‒0.926 0.526 2.075E-03 2.663E-02 AK6 ‒0.925 0.527 9.934E-04 1.556E-02 PREPL ‒0.925 0.527 1.990E-05 8.112E-04 MON1A ‒0.924 0.527 1.628E-03 2.235E-02 NA ‒0.924 0.527 1.399E-03 2.011E-02 UEVLD ‒0.924 0.527 1.906E-04 4.658E-03 IGHV1-2 ‒0.924 0.527 2.565E-03 3.122E-02 SPTLC2 ‒0.923 0.528 1.290E-06 8.310E-05 NCF1B ‒0.921 0.528 2.070E-06 1.247E-04 GGPS1 ‒0.920 0.528 1.520E-06 9.540E-05 RBBP8 ‒0.920 0.529 4.720E-05 1.581E-03 ADRB2 ‒0.917 0.530 4.135E-03 4.321E-02 RHEX ‒0.917 0.530 2.283E-03 2.857E-02 FAM98B ‒0.913 0.531 6.730E-04 1.163E-02 SIT1 ‒0.910 0.532 1.312E-03 1.916E-02 CHST15 ‒0.910 0.532 1.979E-04 4.799E-03 C17orf80 ‒0.910 0.532 1.520E-07 1.390E-05 FGR ‒0.909 0.533 3.613E-04 7.403E-03 C5orf51 ‒0.906 0.534 1.616E-03 2.229E-02 KCTD15 ‒0.905 0.534 2.207E-03 2.792E-02 ANXA4 ‒0.905 0.534 6.878E-04 1.179E-02 HK3 ‒0.904 0.534 1.316E-04 3.469E-03 CPNE5 ‒0.904 0.534 4.818E-03 4.776E-02 RWDD2B ‒0.903 0.535 2.958E-03 3.441E-02 APOBEC3F ‒0.902 0.535 1.834E-03 2.433E-02 KMO ‒0.902 0.535 2.494E-04 5.708E-03 GOLIM4 ‒0.901 0.536 2.739E-03 3.266E-02 CAMK1 ‒0.899 0.536 5.070E-03 4.963E-02 TOR1B ‒0.898 0.537 1.202E-04 3.246E-03 MFAP1 ‒0.898 0.537 1.393E-03 2.004E-02 TMEM106A ‒0.897 0.537 4.068E-04 8.080E-03 PLAGL2 ‒0.897 0.537 3.079E-04 6.603E-03 RHOC ‒0.895 0.538 4.344E-04 8.465E-03 PFKFB4 ‒0.894 0.538 2.956E-03 3.441E-02 KCTD11 ‒0.891 0.539 6.009E-04 1.072E-02 ARCN1 ‒0.891 0.539 2.290E-07 2.010E-05 HAVCR2 ‒0.891 0.539 4.945E-03 4.875E-02 PIK3AP1 ‒0.890 0.539 1.296E-04 3.434E-03 EIF2S1 ‒0.890 0.540 3.690E-07 2.940E-05 NRM ‒0.889 0.540 4.771E-03 4.743E-02 B3GALT4 ‒0.887 0.541 7.940E-05 2.334E-03 DAPK1 ‒0.887 0.541 6.595E-04 1.146E-02 MYD88 ‒0.887 0.541 1.820E-05 7.493E-04 CARD16 ‒0.886 0.541 4.070E-05 1.408E-03 COA3 ‒0.885 0.542 1.571E-03 2.189E-02 MYCBP ‒0.885 0.542 4.448E-04 8.582E-03 PABIR1 ‒0.884 0.542 2.450E-05 9.530E-04 TMEM63C ‒0.884 0.542 3.373E-03 3.762E-02 TMEM250 ‒0.883 0.542 3.470E-05 1.243E-03 IGLV1-51 ‒0.882 0.543 1.730E-03 2.330E-02 TRIM21 ‒0.882 0.543 1.918E-03 2.514E-02 DCLRE1A ‒0.880 0.543 2.415E-03 2.979E-02 PLD4 ‒0.879 0.544 5.697E-04 1.033E-02 GPN3 ‒0.878 0.544 5.717E-04 1.033E-02 HCCS ‒0.877 0.544 8.760E-05 2.517E-03 FIGNL1 ‒0.877 0.545 6.853E-04 1.179E-02 ANKEF1 ‒0.875 0.545 4.877E-03 4.824E-02 ATP23 ‒0.874 0.546 1.076E-03 1.653E-02 ZFP3 ‒0.873 0.546 1.860E-04 4.570E-03 AHCYL1 ‒0.872 0.546 7.540E-05 2.228E-03 CYB561A3 ‒0.870 0.547 3.738E-04 7.576E-03 NDUFAF1 ‒0.868 0.548 7.415E-04 1.248E-02 SP110 ‒0.865 0.549 1.025E-03 1.591E-02 DCAF12 ‒0.865 0.549 3.621E-04 7.403E-03 TOR1A ‒0.864 0.549 5.340E-05 1.737E-03 ZNF816 ‒0.862 0.550 2.478E-03 3.036E-02 CTSC ‒0.861 0.550 4.344E-04 8.465E-03 IL7R ‒0.861 0.551 1.050E-05 4.793E-04 SCRN1 ‒0.860 0.551 8.573E-04 1.387E-02 SNX11 ‒0.860 0.551 3.940E-05 1.374E-03 DUSP7 ‒0.859 0.551 7.930E-04 1.311E-02 TMEM186 ‒0.858 0.552 1.522E-03 2.131E-02 PARP14 ‒0.857 0.552 4.924E-03 4.857E-02 GVINP1 ‒0.857 0.552 6.777E-04 1.169E-02 TXNDC9 ‒0.854 0.553 3.630E-03 3.971E-02 ALAS1 ‒0.853 0.554 1.150E-06 7.630E-05 CDK14 ‒0.850 0.555 2.801E-03 3.307E-02 ZNF737 ‒0.849 0.555 1.275E-04 3.399E-03 VASP ‒0.848 0.555 6.150E-05 1.925E-03 TLR6 ‒0.847 0.556 4.776E-03 4.745E-02 IDH1 ‒0.847 0.556 5.150E-04 9.514E-03 CAMKK2 ‒0.846 0.556 3.040E-05 1.121E-03 GTF2E1 ‒0.846 0.556 3.155E-04 6.722E-03 STT3A ‒0.846 0.556 7.780E-07 5.470E-05 FBXO45 ‒0.845 0.557 4.381E-03 4.500E-02 DPYSL2 ‒0.845 0.557 9.826E-04 1.544E-02 SLC25A19 ‒0.844 0.557 2.963E-04 6.401E-03 MTF1 ‒0.844 0.557 3.516E-04 7.278E-03 DYNC1I2 ‒0.843 0.557 3.290E-06 1.857E-04 MGME1 ‒0.841 0.558 3.640E-06 2.023E-04 CD300A ‒0.840 0.559 4.670E-03 4.684E-02 LIG4 ‒0.838 0.559 1.942E-03 2.536E-02 SNAPC3 ‒0.837 0.560 1.417E-04 3.661E-03 NMT1 ‒0.836 0.560 2.370E-05 9.334E-04 ZW10 ‒0.836 0.560 8.179E-04 1.341E-02 CD244 ‒0.835 0.560 2.957E-04 6.397E-03 ZC3H10 ‒0.835 0.561 2.703E-03 3.238E-02 ZNF226 ‒0.835 0.561 7.200E-06 3.487E-04 CHSY1 ‒0.834 0.561 2.531E-04 5.770E-03 GBP4 ‒0.833 0.561 2.213E-03 2.796E-02 CHCHD4 ‒0.832 0.562 2.198E-03 2.784E-02 SH2B2 ‒0.832 0.562 4.452E-03 4.550E-02 WDR5B ‒0.828 0.563 3.222E-04 6.787E-03 SLC25A24 ‒0.828 0.563 2.719E-03 3.246E-02 TRIM68 ‒0.828 0.563 1.426E-03 2.036E-02 PLPBP ‒0.825 0.565 4.750E-05 1.584E-03 GVQW3 ‒0.824 0.565 1.770E-03 2.368E-02 HSPA8 ‒0.822 0.565 2.737E-04 6.060E-03 CRYZ ‒0.818 0.567 2.996E-04 6.450E-03 DNAJA1 ‒0.818 0.567 3.882E-04 7.840E-03 FASTKD3 ‒0.816 0.568 8.419E-04 1.367E-02 ZKSCAN3 ‒0.814 0.569 2.612E-03 3.163E-02 MTPN ‒0.812 0.570 2.568E-04 5.831E-03 CHMP5 ‒0.812 0.570 3.901E-03 4.162E-02 CTR9 ‒0.811 0.570 6.160E-05 1.925E-03 SNAPIN ‒0.811 0.570 1.112E-04 3.059E-03 SLAMF6 ‒0.807 0.572 8.430E-05 2.444E-03 NMNAT1 ‒0.806 0.572 4.680E-03 4.691E-02 WASF1 ‒0.805 0.572 3.541E-03 3.898E-02 ARMT1 ‒0.804 0.573 4.017E-03 4.246E-02 CHURC1 ‒0.800 0.574 3.104E-03 3.559E-02 RBM6 ‒0.800 0.574 3.925E-04 7.917E-03 DCAF7 ‒0.799 0.575 5.390E-07 3.970E-05 PRDX3 ‒0.799 0.575 2.480E-04 5.700E-03 HSCB ‒0.798 0.575 3.370E-03 3.761E-02 RGS19 ‒0.795 0.576 1.740E-05 7.220E-04 JPT2 ‒0.795 0.577 6.867E-04 1.179E-02 PLXNB2 ‒0.794 0.577 1.454E-03 2.061E-02 SLC35A5 ‒0.793 0.577 2.649E-04 5.947E-03 CD72 ‒0.791 0.578 4.041E-04 8.043E-03 SPRYD3 ‒0.791 0.578 8.190E-05 2.384E-03 DARS2 ‒0.790 0.578 3.140E-04 6.699E-03 ZNF200 ‒0.788 0.579 2.690E-05 1.015E-03 TMOD3 ‒0.787 0.579 1.359E-03 1.970E-02 ARL6IP5 ‒0.787 0.580 1.060E-07 1.040E-05 DCTPP1 ‒0.786 0.580 2.789E-03 3.295E-02 CALML4 ‒0.786 0.580 4.506E-03 4.589E-02 YWHAG ‒0.786 0.580 2.025E-03 2.618E-02 TMBIM1 ‒0.782 0.581 2.160E-06 1.273E-04 VKORC1L1 ‒0.779 0.583 1.136E-04 3.103E-03 CNP ‒0.778 0.583 3.691E-03 4.011E-02 CAP1 ‒0.776 0.584 2.844E-04 6.234E-03 ZNF234 ‒0.775 0.584 1.437E-04 3.706E-03 BASP1 ‒0.773 0.585 5.920E-05 1.881E-03 TBC1D24 ‒0.771 0.586 1.164E-03 1.754E-02 AHSA1 ‒0.771 0.586 4.257E-04 8.354E-03 LAMP2 ‒0.769 0.587 1.589E-04 4.006E-03 SYK ‒0.769 0.587 2.178E-03 2.772E-02 MRPS18B ‒0.769 0.587 1.626E-03 2.235E-02 TARS1 ‒0.769 0.587 4.520E-05 1.530E-03 MCMBP ‒0.768 0.587 6.120E-05 1.921E-03 OSTM1 ‒0.768 0.587 4.755E-04 8.963E-03 CD53 ‒0.767 0.588 1.440E-05 6.211E-04 EVI2A ‒0.767 0.588 4.626E-04 8.797E-03 B4GALT5 ‒0.765 0.588 1.846E-03 2.443E-02 TXLNA ‒0.763 0.589 1.096E-04 3.023E-03 JAK2 ‒0.763 0.589 6.770E-05 2.063E-03 TPP1 ‒0.763 0.589 3.500E-03 3.861E-02 BPNT1 ‒0.762 0.590 3.441E-03 3.811E-02 NDUFA8 ‒0.762 0.590 2.972E-03 3.453E-02 HLA-DOA ‒0.762 0.590 1.671E-04 4.181E-03 TAPBPL ‒0.762 0.590 2.182E-03 2.772E-02 GIMAP6 ‒0.759 0.591 3.270E-05 1.186E-03 SLC35C1 ‒0.759 0.591 2.860E-03 3.360E-02 UBXN2B ‒0.756 0.592 2.081E-04 5.003E-03 ZNF397 ‒0.756 0.592 3.820E-07 2.990E-05 CEP89 ‒0.756 0.592 3.606E-03 3.958E-02 PARP4 ‒0.755 0.593 2.203E-04 5.215E-03 GSTO1 ‒0.754 0.593 8.860E-05 2.537E-03 IRF2 ‒0.754 0.593 5.590E-06 2.835E-04 VPS41 ‒0.753 0.593 1.407E-03 2.013E-02 ZNF213 ‒0.753 0.593 3.088E-03 3.548E-02 TRIM27 ‒0.753 0.594 1.370E-06 8.750E-05 YIPF4 ‒0.752 0.594 5.883E-04 1.055E-02 ACADM ‒0.752 0.594 2.713E-03 3.243E-02 CAPZA2 ‒0.751 0.594 6.572E-04 1.144E-02 ZKSCAN4 ‒0.749 0.595 1.423E-03 2.033E-02 ZNF780B ‒0.749 0.595 7.360E-05 2.194E-03 TNFAIP1 ‒0.748 0.595 2.610E-04 5.901E-03 NFE2L1 ‒0.748 0.596 8.379E-04 1.362E-02 HLA-DPA1 ‒0.747 0.596 5.163E-04 9.526E-03 GYG1 ‒0.746 0.596 1.608E-03 2.225E-02 PURA ‒0.744 0.597 2.421E-04 5.602E-03 LFNG ‒0.743 0.598 1.014E-03 1.581E-02 C11orf68 ‒0.742 0.598 7.261E-04 1.231E-02 C2orf42 ‒0.740 0.599 2.705E-03 3.238E-02 GID4 ‒0.739 0.599 1.028E-04 2.875E-03 CCDC117 ‒0.738 0.600 1.763E-03 2.363E-02 TSPAN31 ‒0.737 0.600 1.678E-03 2.281E-02 PRUNE1 ‒0.735 0.601 4.325E-04 8.457E-03 SWAP70 ‒0.734 0.601 2.087E-04 5.011E-03 THRAP3 ‒0.731 0.602 8.680E-08 8.770E-06 MOB3C ‒0.730 0.603 3.011E-03 3.486E-02 RAB8A ‒0.730 0.603 1.505E-04 3.858E-03 RNGTT ‒0.729 0.603 4.728E-03 4.716E-02 MRPL15 ‒0.726 0.605 4.012E-04 8.025E-03 DHRS7 ‒0.724 0.606 3.188E-04 6.754E-03 C1GALT1C1 ‒0.723 0.606 3.879E-03 4.146E-02 ZNF146 ‒0.723 0.606 2.930E-07 2.440E-05 SDF2 ‒0.723 0.606 2.940E-04 6.372E-03 IFNGR2 ‒0.722 0.606 4.709E-04 8.916E-03 E2F5 ‒0.722 0.606 9.697E-04 1.533E-02 HVCN1 ‒0.721 0.606 3.394E-04 7.077E-03 JKAMP ‒0.721 0.607 1.312E-03 1.916E-02 PRKCD ‒0.720 0.607 7.843E-04 1.303E-02 RP2 ‒0.719 0.608 3.960E-03 4.203E-02 STIP1 ‒0.717 0.608 6.692E-04 1.159E-02 ORMDL2 ‒0.717 0.608 1.371E-03 1.977E-02 SHMT1 ‒0.716 0.609 1.467E-03 2.074E-02 SLC25A20 ‒0.716 0.609 5.278E-04 9.664E-03 HSBP1 ‒0.715 0.609 1.230E-04 3.306E-03 CTSH ‒0.714 0.610 1.713E-03 2.314E-02 ARPC5 ‒0.713 0.610 1.708E-04 4.253E-03 LARS2 ‒0.712 0.611 2.247E-04 5.287E-03 DOK3 ‒0.711 0.611 2.647E-03 3.192E-02 BRD8 ‒0.710 0.611 4.840E-07 3.630E-05 NEK4 ‒0.708 0.612 2.598E-03 3.152E-02 RBM4B ‒0.707 0.612 6.340E-04 1.114E-02 ZBTB7B ‒0.707 0.612 7.401E-04 1.247E-02 SLC35B3 ‒0.704 0.614 3.171E-04 6.739E-03 HAT1 ‒0.704 0.614 3.129E-03 3.569E-02 GIMAP2 ‒0.704 0.614 2.470E-07 2.110E-05 ATP6V0E1 ‒0.704 0.614 1.282E-04 3.411E-03 SNX27 ‒0.703 0.614 1.127E-03 1.711E-02 PDCD7 ‒0.703 0.614 2.816E-04 6.198E-03 ECHDC1 ‒0.702 0.615 4.178E-04 8.248E-03 ZNF486 ‒0.701 0.615 4.571E-03 4.624E-02 MTREX ‒0.699 0.616 2.644E-04 5.947E-03 SNX19 ‒0.697 0.617 2.376E-03 2.940E-02 OMA1 ‒0.697 0.617 7.030E-05 2.113E-03 DLAT ‒0.696 0.617 4.279E-03 4.420E-02 RPP25L ‒0.695 0.618 2.389E-03 2.950E-02 VEZT ‒0.693 0.619 5.126E-04 9.478E-03 OGFOD1 ‒0.690 0.620 1.115E-03 1.699E-02 TTI2 ‒0.690 0.620 4.590E-03 4.630E-02 TBL2 ‒0.689 0.620 1.505E-04 3.858E-03 ZNF608 ‒0.688 0.621 2.782E-03 3.295E-02 UBE4A ‒0.687 0.621 3.200E-05 1.165E-03 MCEE ‒0.687 0.621 2.028E-03 2.620E-02 DAXX ‒0.686 0.622 3.421E-04 7.124E-03 IFNAR1 ‒0.685 0.622 2.224E-04 5.241E-03 PAXIP1-AS2 ‒0.683 0.623 1.178E-03 1.771E-02 TOLLIP ‒0.683 0.623 2.260E-05 9.004E-04 BUD13 ‒0.683 0.623 4.870E-05 1.615E-03 TIA1 ‒0.682 0.623 5.530E-06 2.817E-04 PCMT1 ‒0.682 0.623 7.390E-05 2.200E-03 ATP6V0D1 ‒0.682 0.624 1.010E-04 2.837E-03 HSD17B4 ‒0.680 0.624 1.400E-05 6.077E-04 LAIR1 ‒0.680 0.624 4.060E-05 1.405E-03 ITGAX ‒0.679 0.624 9.025E-04 1.444E-02 RITA1 ‒0.679 0.625 6.116E-04 1.087E-02 SFT2D1 ‒0.679 0.625 9.540E-05 2.694E-03 UTP6 ‒0.679 0.625 1.660E-05 6.972E-04 CNIH4 ‒0.678 0.625 1.843E-04 4.542E-03 LYN ‒0.677 0.625 4.031E-04 8.043E-03 CTNND1 ‒0.675 0.626 1.995E-03 2.590E-02 PSMB8-AS1 ‒0.675 0.626 1.674E-03 2.279E-02 REEP5 ‒0.675 0.627 1.024E-03 1.591E-02 TLR1 ‒0.674 0.627 3.392E-03 3.776E-02 MGAT2 ‒0.673 0.627 8.250E-04 1.346E-02 CRKL ‒0.670 0.628 3.963E-04 7.965E-03 SLC49A3 ‒0.670 0.629 3.924E-03 4.173E-02 SEC23IP ‒0.668 0.629 1.127E-04 3.089E-03 NADK ‒0.668 0.630 1.154E-03 1.744E-02 HSPH1 ‒0.666 0.630 7.160E-05 2.136E-03 GPR65 ‒0.665 0.631 1.014E-03 1.581E-02 APEX2 ‒0.665 0.631 4.314E-03 4.450E-02 CPLANE1 ‒0.664 0.631 3.376E-03 3.762E-02 MAP1S ‒0.663 0.631 1.552E-03 2.168E-02 SNAPC5 ‒0.663 0.632 1.127E-03 1.711E-02 HLA-DPB1 ‒0.663 0.632 3.619E-04 7.403E-03 APOBEC3D ‒0.661 0.633 6.868E-04 1.179E-02 LYSMD2 ‒0.660 0.633 1.488E-03 2.095E-02 FCMR ‒0.660 0.633 5.730E-07 4.150E-05 ZBTB38 ‒0.659 0.633 1.204E-04 3.246E-03 GDI2 ‒0.659 0.633 6.120E-04 1.087E-02 VTA1 ‒0.657 0.634 7.080E-04 1.207E-02 MR1 ‒0.654 0.635 7.883E-04 1.306E-02 ICAM2 ‒0.654 0.635 3.458E-03 3.826E-02 PHF11 ‒0.653 0.636 1.591E-03 2.213E-02 ACTR2 ‒0.652 0.636 5.789E-04 1.044E-02 CRLS1 ‒0.650 0.637 4.520E-04 8.652E-03 GM2A ‒0.649 0.638 9.820E-04 1.544E-02 SLC2A6 ‒0.648 0.638 1.200E-06 7.840E-05 MARCHF7 ‒0.648 0.638 2.294E-03 2.863E-02 ALOX5AP ‒0.646 0.639 3.902E-03 4.162E-02 COX15 ‒0.646 0.639 1.360E-03 1.970E-02 DOCK8 ‒0.646 0.639 1.360E-05 5.939E-04 TRIM4 ‒0.644 0.640 7.500E-06 3.611E-04 ILK ‒0.644 0.640 1.388E-04 3.601E-03 LCP1 ‒0.643 0.640 4.403E-03 4.518E-02 CLTA ‒0.642 0.641 1.195E-04 3.237E-03 IL10RB ‒0.640 0.642 3.723E-03 4.034E-02 TMBIM6 ‒0.639 0.642 2.440E-05 9.504E-04 TIMMDC1 ‒0.639 0.642 1.759E-04 4.362E-03 HEIH ‒0.638 0.643 3.753E-04 7.598E-03 DENND5B ‒0.638 0.643 6.972E-04 1.191E-02 PPP1R11 ‒0.638 0.643 2.980E-05 1.109E-03 UBE2V2 ‒0.637 0.643 2.890E-04 6.312E-03 C11orf24 ‒0.637 0.643 2.280E-03 2.857E-02 NME6 ‒0.636 0.643 3.406E-03 3.785E-02 BIRC2 ‒0.636 0.643 6.780E-05 2.063E-03 NIT1 ‒0.636 0.644 1.581E-04 3.997E-03 ACTR1A ‒0.635 0.644 1.921E-03 2.517E-02 ZNF260 ‒0.635 0.644 2.911E-03 3.415E-02 C21orf91 ‒0.634 0.644 2.697E-04 5.994E-03 COPB2 ‒0.633 0.645 1.357E-04 3.539E-03 VCL ‒0.632 0.645 4.889E-03 4.832E-02 FRAT1 ‒0.630 0.646 4.730E-04 8.934E-03 S100A4 ‒0.630 0.646 3.008E-03 3.486E-02 AIMP2 ‒0.629 0.647 2.159E-03 2.752E-02 CREBL2 ‒0.629 0.647 2.557E-03 3.114E-02 RNF5 ‒0.627 0.647 7.217E-04 1.225E-02 AHNAK ‒0.627 0.647 4.531E-03 4.603E-02 AFTPH ‒0.626 0.648 2.755E-03 3.276E-02 KRCC1 ‒0.625 0.648 1.733E-04 4.303E-03 BLNK ‒0.625 0.648 4.971E-03 4.889E-02 ETFA ‒0.623 0.649 1.257E-04 3.368E-03 SP1 ‒0.622 0.650 1.998E-03 2.592E-02 AMMECR1L ‒0.621 0.650 2.412E-04 5.588E-03 MITD1 ‒0.621 0.650 1.673E-03 2.279E-02 MRS2 ‒0.620 0.651 1.214E-03 1.810E-02 GRK3 ‒0.619 0.651 4.105E-03 4.302E-02 SNX20 ‒0.618 0.651 5.810E-05 1.862E-03 PTPN6 ‒0.618 0.652 3.015E-04 6.473E-03 ZKSCAN1 ‒0.618 0.652 3.728E-04 7.566E-03 NIPA2 ‒0.617 0.652 2.034E-03 2.625E-02 POC5 ‒0.616 0.652 8.359E-04 1.360E-02 CCT5 ‒0.616 0.653 1.356E-04 3.539E-03 ANXA1 ‒0.616 0.653 4.253E-03 4.404E-02 FGFR1OP2 ‒0.614 0.653 3.125E-04 6.675E-03 MED12 ‒0.614 0.653 3.740E-05 1.314E-03 ZNF672 ‒0.613 0.654 1.240E-03 1.833E-02 RPE ‒0.611 0.655 6.204E-04 1.096E-02 COPS4 ‒0.610 0.655 7.730E-04 1.289E-02 FXR2 ‒0.610 0.655 2.358E-04 5.502E-03 COP1 ‒0.610 0.655 1.446E-03 2.053E-02 DENND2D ‒0.609 0.656 1.316E-03 1.921E-02 FUCA1 ‒0.609 0.656 9.178E-04 1.465E-02 KRBOX4 ‒0.607 0.656 1.301E-03 1.907E-02 MAT2B ‒0.603 0.658 1.130E-05 5.131E-04 NUP62 ‒0.603 0.659 7.100E-05 2.122E-03 NA ‒0.602 0.659 3.171E-03 3.599E-02 MTHFD2 ‒0.602 0.659 4.403E-04 8.540E-03 ZNF721 ‒0.601 0.659 5.302E-04 9.696E-03 HERC2P2 ‒0.601 0.659 3.240E-06 1.834E-04 MSANTD4 ‒0.600 0.660 4.577E-03 4.625E-02 DNAJC7 ‒0.600 0.660 3.606E-04 7.403E-03 ELF4 ‒0.600 0.660 2.594E-03 3.152E-02 GLT8D1 ‒0.599 0.660 6.020E-05 1.898E-03 SPIDR ‒0.599 0.660 3.138E-03 3.577E-02 NLRX1 ‒0.599 0.660 4.019E-03 4.246E-02 ACTR3 ‒0.598 0.661 1.266E-04 3.380E-03 ZNF175 ‒0.597 0.661 4.158E-03 4.334E-02 NDUFB3 ‒0.596 0.662 7.103E-04 1.209E-02 SH2D3C ‒0.596 0.662 3.037E-03 3.504E-02 ZNF197 ‒0.596 0.662 4.523E-04 8.652E-03 UMPS ‒0.595 0.662 2.930E-03 3.423E-02 SEPHS2 ‒0.594 0.662 3.244E-03 3.660E-02 ZNF586 ‒0.594 0.662 1.264E-04 3.380E-03 LEO1 ‒0.594 0.663 3.921E-03 4.173E-02 RAC2 ‒0.593 0.663 3.166E-03 3.596E-02 SLC16A3 ‒0.593 0.663 2.532E-04 5.770E-03 PPP1R8 ‒0.592 0.663 3.268E-03 3.675E-02 RBL2 ‒0.592 0.664 3.084E-04 6.605E-03 ABRACL ‒0.591 0.664 2.282E-03 2.857E-02 ARFIP1 ‒0.590 0.664 4.555E-03 4.613E-02 KLHL9 ‒0.590 0.664 8.259E-04 1.346E-02 TBC1D1 ‒0.589 0.665 1.603E-03 2.224E-02 AGTRAP ‒0.588 0.665 1.624E-03 2.235E-02 MICB ‒0.588 0.665 4.557E-03 4.613E-02 ASH2L ‒0.587 0.666 3.380E-05 1.215E-03 RTCB ‒0.586 0.666 1.095E-03 1.674E-02 MRM3 0.587 1.503 2.585E-03 3.143E-02 HNRNPA1 0.588 1.503 2.640E-05 1.007E-03 REXO1 0.589 1.504 4.524E-03 4.599E-02 TRA2B 0.589 1.505 2.448E-04 5.648E-03 EME2 0.590 1.505 3.269E-03 3.675E-02 DDX51 0.592 1.507 9.971E-04 1.558E-02 CHD1 0.592 1.508 1.627E-03 2.235E-02 MED9 0.592 1.508 4.072E-03 4.282E-02 ASNS 0.593 1.508 2.197E-04 5.207E-03 ZNF831 0.596 1.511 3.658E-04 7.469E-03 CLDND1 0.599 1.514 3.464E-04 7.188E-03 FBXO32 0.601 1.516 2.468E-03 3.026E-02 SREBF1 0.603 1.519 2.245E-03 2.829E-02 GMFB 0.604 1.519 1.149E-03 1.739E-02 ATN1 0.605 1.521 1.502E-03 2.112E-02 DNAJB14 0.606 1.522 2.373E-03 2.940E-02 KANSL2 0.606 1.522 4.408E-04 8.540E-03 MLLT3 0.609 1.525 1.763E-04 4.365E-03 KLF11 0.609 1.525 4.225E-03 4.389E-02 FOXP1 0.610 1.526 5.710E-05 1.833E-03 MZT2B 0.611 1.527 4.147E-03 4.330E-02 NOP53 0.612 1.528 3.736E-03 4.040E-02 POU2F1 0.612 1.528 1.041E-04 2.900E-03 RFX3 0.612 1.529 7.849E-04 1.303E-02 KRR1 0.617 1.534 4.080E-06 2.210E-04 SSBP1 0.617 1.534 6.140E-06 3.038E-04 MCRIP2 0.619 1.536 1.407E-03 2.013E-02 LRP5L 0.620 1.537 3.344E-03 3.739E-02 LEMD3 0.621 1.537 4.250E-06 2.286E-04 MEF2D 0.621 1.538 9.140E-07 6.240E-05 ENSG00000261490 0.621 1.538 3.129E-03 3.569E-02 PAG1 0.622 1.539 7.514E-04 1.261E-02 CCDC57 0.623 1.540 4.723E-04 8.933E-03 PRDM2 0.623 1.540 2.620E-05 1.002E-03 SFXN1 0.624 1.541 1.611E-03 2.228E-02 FRS2 0.625 1.542 2.355E-03 2.924E-02 SGMS1 0.625 1.542 2.255E-03 2.833E-02 H1-10 0.626 1.544 3.870E-06 2.106E-04 INTS1 0.626 1.544 1.236E-03 1.831E-02 TRERF1 0.631 1.549 1.605E-03 2.225E-02 PPP1R15A 0.632 1.549 1.870E-05 7.664E-04 RHNO1 0.635 1.553 3.557E-03 3.912E-02 ANAPC15 0.635 1.553 1.214E-04 3.267E-03 SLC5A6 0.636 1.554 4.500E-06 2.390E-04 COX4I1 0.637 1.555 8.740E-08 8.770E-06 MRPL44 0.637 1.555 3.803E-04 7.690E-03 FBXL3 0.638 1.556 4.040E-05 1.404E-03 LCOR 0.639 1.557 5.050E-06 2.628E-04 TGIF1 0.641 1.560 3.228E-03 3.649E-02 FKBP11 0.642 1.560 1.951E-03 2.542E-02 KDM7A 0.642 1.560 2.144E-04 5.111E-03 SNHG16 0.643 1.562 2.941E-04 6.372E-03 SNRK 0.644 1.562 5.018E-04 9.348E-03 SLC25A36 0.644 1.563 4.191E-04 8.263E-03 SUPV3L1 0.644 1.563 5.874E-04 1.055E-02 PNMA1 0.644 1.563 4.122E-03 4.314E-02 PAFAH1B2 0.644 1.563 1.967E-04 4.783E-03 ATG2A 0.645 1.564 7.069E-04 1.207E-02 ELF2 0.646 1.565 2.100E-06 1.258E-04 FAM229A 0.646 1.565 4.983E-03 4.899E-02 ATF4 0.647 1.566 3.570E-05 1.269E-03 FAM102A 0.648 1.567 2.165E-03 2.757E-02 EAF1 0.649 1.569 1.721E-03 2.321E-02 TMEM120B 0.650 1.570 3.680E-03 4.004E-02 ARID2 0.652 1.572 3.384E-04 7.066E-03 TRIM52-AS1 0.654 1.573 2.059E-03 2.645E-02 RPS14 0.654 1.574 2.686E-04 5.994E-03 NFKBIE 0.655 1.574 5.094E-03 4.981E-02 MEGF6 0.655 1.574 1.771E-03 2.368E-02 SNRPA1 0.658 1.578 1.883E-04 4.620E-03 LMTK2 0.658 1.578 2.750E-05 1.027E-03 NSMCE3 0.659 1.579 2.660E-05 1.008E-03 EPB41L4A-AS1 0.660 1.580 2.530E-05 9.788E-04 POU6F1 0.661 1.581 1.190E-03 1.785E-02 ENSG00000257354 0.662 1.582 3.623E-03 3.971E-02 ZNF408 0.662 1.583 2.807E-03 3.310E-02 CHD7 0.662 1.583 1.470E-04 3.785E-03 ZNF432 0.663 1.583 1.236E-03 1.831E-02 B3GNTL1 0.663 1.583 7.535E-04 1.263E-02 NFKBIZ 0.665 1.585 3.061E-03 3.526E-02 NFKBIB 0.666 1.587 6.410E-04 1.123E-02 BICDL1 0.666 1.587 4.001E-04 8.013E-03 PIK3R1 0.668 1.589 1.102E-03 1.682E-02 KAT6B 0.668 1.589 2.580E-05 9.886E-04 IGF1R 0.669 1.589 1.102E-03 1.682E-02 BTG2 0.669 1.590 2.494E-04 5.708E-03 LEPROTL1 0.670 1.591 1.651E-03 2.256E-02 NECAP1 0.670 1.591 1.750E-06 1.078E-04 AP1G2-AS1 0.672 1.593 4.120E-05 1.420E-03 SVIP 0.674 1.595 9.720E-04 1.535E-02 ISCA1 0.675 1.596 1.640E-03 2.245E-02 PNRC1 0.675 1.597 7.980E-06 3.809E-04 PIDD1 0.678 1.600 8.583E-04 1.387E-02 VAMP2 0.679 1.601 1.820E-08 2.020E-06 ADAMTS10 0.680 1.602 4.540E-03 4.607E-02 TCF7 0.682 1.604 1.200E-05 5.353E-04 EXD3 0.683 1.605 1.214E-03 1.810E-02 TIAM1 0.683 1.605 3.855E-03 4.133E-02 LINC-PINT 0.686 1.609 2.743E-03 3.266E-02 ATXN1L 0.689 1.613 8.960E-05 2.560E-03 MBIP 0.691 1.615 2.098E-03 2.688E-02 NOL4L 0.692 1.615 4.613E-04 8.783E-03 RPL36A 0.692 1.616 3.688E-03 4.011E-02 VCPKMT 0.693 1.616 6.204E-04 1.096E-02 CBX6 0.693 1.617 2.331E-04 5.460E-03 MRPL41 0.695 1.618 3.350E-03 3.744E-02 ENSG00000280135 0.695 1.618 2.653E-03 3.196E-02 ADNP2 0.695 1.619 1.100E-05 4.997E-04 ZNF800 0.701 1.626 3.030E-05 1.118E-03 EPHB4 0.704 1.629 2.807E-03 3.310E-02 EIF5 0.705 1.630 1.960E-06 1.186E-04 PGM2L1 0.705 1.630 3.167E-04 6.738E-03 DYNLT1 0.706 1.631 3.925E-03 4.173E-02 CNNM2 0.706 1.631 6.423E-04 1.124E-02 PPIL4 0.707 1.632 2.334E-03 2.902E-02 TRMO 0.707 1.633 1.910E-03 2.506E-02 HIVEP1 0.707 1.633 1.326E-04 3.484E-03 BEX4 0.708 1.633 2.802E-04 6.175E-03 MRPL9 0.708 1.634 1.324E-04 3.484E-03 TLE2 0.710 1.636 3.869E-03 4.140E-02 EIF1B 0.712 1.638 8.150E-05 2.379E-03 SNHG1 0.712 1.638 1.213E-03 1.810E-02 ZNF814 0.714 1.640 2.058E-04 4.963E-03 ENSG00000230551 0.715 1.642 4.259E-03 4.407E-02 GOLT1B 0.716 1.642 1.880E-03 2.473E-02 MFGE8 0.717 1.644 1.714E-03 2.314E-02 RICTOR 0.718 1.645 1.176E-04 3.195E-03 UTP15 0.719 1.646 1.959E-04 4.771E-03 SIVA1 0.720 1.647 1.090E-04 3.014E-03 SORBS3 0.723 1.650 9.648E-04 1.527E-02 EMD 0.724 1.652 2.687E-04 5.994E-03 TRABD 0.727 1.655 6.177E-04 1.094E-02 EIF2AK3 0.727 1.655 2.914E-04 6.346E-03 ZNF134 0.727 1.655 4.069E-04 8.080E-03 PIK3IP1 0.728 1.656 2.966E-04 6.401E-03 NCBP2AS2 0.728 1.656 5.660E-05 1.821E-03 DDX39A 0.729 1.658 1.020E-04 2.857E-03 PHF1 0.731 1.660 2.120E-05 8.495E-04 ARRDC2 0.732 1.661 1.644E-03 2.249E-02 GABARAPL1 0.733 1.663 1.934E-03 2.528E-02 SRSF10 0.737 1.666 5.980E-06 2.990E-04 CHRM3-AS2 0.737 1.666 1.470E-03 2.076E-02 ZNF815P 0.739 1.669 4.427E-04 8.558E-03 MGST3 0.742 1.672 1.709E-03 2.314E-02 AP3M2 0.742 1.672 4.388E-03 4.505E-02 JOSD1 0.743 1.673 1.210E-06 7.880E-05 ODC1 0.743 1.674 2.740E-05 1.027E-03 KPNA5 0.749 1.680 4.024E-04 8.039E-03 GOLGA7B 0.753 1.685 1.060E-03 1.632E-02 MAP3K1 0.755 1.688 3.930E-04 7.918E-03 AK5 0.756 1.689 2.327E-04 5.460E-03 C5orf24 0.756 1.689 6.860E-07 4.840E-05 KLHL24 0.758 1.691 2.270E-05 9.013E-04 TAF3 0.759 1.692 1.870E-05 7.668E-04 FAM160B1 0.760 1.693 1.333E-04 3.498E-03 BICRA 0.760 1.693 2.379E-04 5.529E-03 AKT1S1 0.761 1.695 8.010E-05 2.345E-03 RLIM 0.763 1.697 1.340E-06 8.610E-05 MAPKAPK5-AS1 0.768 1.703 2.970E-07 2.470E-05 NA 0.772 1.707 4.109E-03 4.303E-02 KLHL15 0.772 1.707 3.060E-05 1.127E-03 TIPARP 0.776 1.713 1.574E-04 3.991E-03 FAM177A1 0.776 1.713 2.670E-04 5.980E-03 CIDECP1 0.778 1.715 4.942E-04 9.244E-03 MTHFD2L 0.778 1.715 2.120E-03 2.710E-02 NPIPB5 0.780 1.717 3.472E-03 3.836E-02 LMO7 0.781 1.718 5.950E-06 2.985E-04 NOXA1 0.781 1.718 2.253E-03 2.832E-02 TMEM201 0.782 1.719 6.646E-04 1.153E-02 PPP1R32 0.782 1.720 2.050E-03 2.637E-02 IL1B 0.783 1.720 1.594E-03 2.215E-02 MYL5 0.783 1.720 2.121E-03 2.710E-02 ENSG00000264112 0.787 1.726 2.120E-06 1.266E-04 ENSG00000279838 0.789 1.728 4.723E-03 4.716E-02 ZNF805 0.789 1.728 2.189E-04 5.196E-03 CLK1 0.790 1.729 4.560E-10 8.260E-08 PTS 0.791 1.730 3.444E-03 3.813E-02 RNF125 0.791 1.731 3.585E-04 7.393E-03 PSTK 0.792 1.732 3.158E-03 3.592E-02 FOXK1 0.795 1.735 8.360E-06 3.911E-04 SOX12 0.796 1.736 1.260E-06 8.130E-05 ZNF446 0.796 1.736 2.381E-03 2.943E-02 MBNL2 0.796 1.737 1.530E-05 6.520E-04 SNHG20 0.796 1.737 6.018E-04 1.072E-02 RAMAC 0.798 1.738 2.212E-03 2.796E-02 NA 0.798 1.739 1.333E-03 1.940E-02 NFKBID 0.799 1.740 1.740E-05 7.220E-04 HBP1 0.800 1.741 7.925E-04 1.311E-02 CHIC1 0.805 1.747 8.110E-05 2.370E-03 ISCU 0.805 1.747 4.390E-06 2.343E-04 SGTB 0.807 1.750 7.781E-04 1.296E-02 TRAF4 0.809 1.752 3.730E-05 1.313E-03 ZFP36 0.811 1.754 1.494E-04 3.841E-03 EPHA4 0.812 1.755 1.045E-04 2.908E-03 CDK11A 0.812 1.756 1.310E-05 5.747E-04 ANO9 0.813 1.757 2.292E-03 2.863E-02 TYW5 0.815 1.760 4.949E-04 9.244E-03 RETREG1 0.819 1.764 5.862E-04 1.054E-02 CD28 0.822 1.768 6.437E-04 1.125E-02 KDM6B 0.826 1.772 4.410E-07 3.380E-05 ARL5B 0.826 1.773 3.616E-04 7.403E-03 SLC2A4RG 0.826 1.773 5.712E-04 1.033E-02 PET100 0.831 1.779 6.930E-05 2.095E-03 ZFYVE28 0.835 1.784 1.633E-03 2.237E-02 ZNF587B 0.837 1.787 2.430E-05 9.504E-04 PLCL1 0.847 1.799 1.886E-03 2.478E-02 SMURF1 0.850 1.802 5.870E-05 1.873E-03 DDX24 0.850 1.802 2.100E-07 1.860E-05 STARD10 0.853 1.806 2.916E-03 3.416E-02 POLR1C 0.853 1.806 8.020E-06 3.816E-04 TIGD1 0.855 1.809 2.612E-03 3.163E-02 EIF1 0.855 1.809 4.610E-06 2.439E-04 HMGB2 0.856 1.810 7.320E-06 3.536E-04 ENSG00000272529 0.856 1.810 5.188E-04 9.551E-03 H3-3B 0.856 1.811 7.380E-09 9.680E-07 ENSG00000235859 0.857 1.812 1.711E-03 2.314E-02 CEP85L 0.858 1.812 2.426E-03 2.982E-02 RBM7 0.859 1.814 5.269E-04 9.661E-03 LRRC8B 0.862 1.817 6.560E-06 3.205E-04 RASGEF1B 0.862 1.818 1.402E-04 3.632E-03 CNBD2 0.863 1.819 6.823E-04 1.176E-02 OTUD1 0.863 1.819 6.160E-06 3.038E-04 BCL10 0.863 1.819 1.669E-04 4.181E-03 P2RY11 0.864 1.820 1.428E-03 2.037E-02 ZNF844 0.869 1.826 7.990E-08 8.120E-06 NGDN 0.871 1.829 1.550E-08 1.760E-06 ENO2 0.874 1.833 2.610E-04 5.901E-03 ENSG00000271964 0.876 1.836 1.054E-03 1.625E-02 AMMECR1 0.877 1.837 3.840E-06 2.096E-04 YPEL5 0.880 1.840 3.000E-07 2.470E-05 MGAT4A 0.881 1.841 1.650E-05 6.972E-04 HSF2 0.881 1.842 7.080E-05 2.121E-03 ZXDB 0.882 1.843 6.000E-05 1.895E-03 ZEB1 0.884 1.846 2.760E-06 1.599E-04 HAGHL 0.886 1.847 2.784E-03 3.295E-02 AEN 0.886 1.847 4.430E-07 3.390E-05 MYLIP 0.886 1.849 3.070E-07 2.510E-05 IER2 0.888 1.851 9.330E-08 9.310E-06 ENSG00000261526 0.889 1.852 1.907E-04 4.658E-03 GZF1 0.890 1.853 9.380E-05 2.668E-03 PMAIP1 0.890 1.854 4.041E-03 4.256E-02 RHPN1 0.894 1.859 2.180E-03 2.772E-02 MAST4 0.894 1.859 4.650E-04 8.823E-03 ZFAND2A 0.899 1.865 4.370E-06 2.341E-04 ZNF628 0.900 1.866 2.684E-03 3.222E-02 ASMTL-AS1 0.902 1.869 8.460E-06 3.950E-04 ZBTB20 0.907 1.875 1.534E-03 2.146E-02 CYP4V2 0.908 1.877 1.304E-04 3.449E-03 SETD1B 0.912 1.881 3.430E-10 6.580E-08 NXT1 0.912 1.881 3.860E-05 1.348E-03 IL6ST 0.912 1.882 5.010E-05 1.654E-03 ENSG00000269688 0.912 1.882 8.641E-04 1.395E-02 CTSK 0.915 1.885 5.841E-04 1.052E-02 GLUD1P3 0.915 1.886 4.271E-03 4.417E-02 SCNN1D 0.916 1.887 9.470E-05 2.687E-03 ENSG00000232545 0.917 1.888 5.076E-03 4.966E-02 ZXDA 0.917 1.888 1.152E-04 3.141E-03 KLHL11 0.919 1.891 1.652E-03 2.256E-02 SNIP1 0.920 1.893 3.196E-04 6.754E-03 EDAR 0.922 1.895 1.294E-03 1.899E-02 ABCD2 0.926 1.900 1.365E-04 3.547E-03 ZNF256 0.927 1.901 2.885E-04 6.312E-03 ANTXRLP1 0.927 1.902 1.811E-03 2.410E-02 WDR74 0.929 1.904 9.700E-05 2.734E-03 GPRASP1 0.930 1.905 4.769E-04 8.968E-03 LINC00852 0.930 1.905 6.850E-05 2.074E-03 FASTKD5 0.931 1.907 6.630E-07 4.720E-05 MOAP1 0.933 1.909 4.620E-09 6.270E-07 TADA1 0.936 1.913 3.640E-05 1.289E-03 PPIF 0.936 1.913 3.520E-06 1.973E-04 MATR3 0.938 1.916 2.239E-03 2.826E-02 PDE4B 0.940 1.918 2.000E-05 8.122E-04 NLRP6 0.940 1.919 5.945E-04 1.063E-02 RAB33B-AS1 0.945 1.925 3.465E-03 3.830E-02 DBF4 0.946 1.927 2.925E-04 6.362E-03 IRF2BP2 0.947 1.928 1.140E-09 1.810E-07 CCNT1 0.951 1.933 5.740E-10 9.970E-08 SNPH 0.951 1.933 4.021E-03 4.246E-02 YRDC 0.953 1.936 5.730E-06 2.887E-04 FEM1C 0.954 1.937 2.130E-06 1.266E-04 LINC00641 0.959 1.945 2.500E-05 9.710E-04 CCNL1 0.961 1.947 1.930E-09 2.870E-07 ZNF101 0.961 1.947 1.640E-05 6.936E-04 MIRLET7A1HG 0.963 1.949 2.058E-04 4.963E-03 CDR2 0.963 1.950 1.849E-04 4.551E-03 ZNF639 0.964 1.951 8.050E-09 1.040E-06 DOC2GP 0.965 1.952 1.507E-03 2.115E-02 DCTN6 0.967 1.955 1.254E-03 1.847E-02 DNAJB9 0.968 1.957 3.380E-05 1.215E-03 CREBRF 0.973 1.963 6.470E-09 8.560E-07 TBKBP1 0.978 1.970 6.293E-04 1.109E-02 CCDC85C 0.980 1.972 2.530E-03 3.092E-02 MAFK 0.984 1.979 1.150E-06 7.630E-05 SLC22A23 0.985 1.979 1.410E-06 8.930E-05 DUSP5 0.993 1.990 6.290E-05 1.950E-03 SNHG8 1.001 2.002 6.127E-04 1.087E-02 MIR23AHG 1.002 2.003 1.224E-03 1.820E-02 ENSG00000259623 1.006 2.008 1.670E-05 6.989E-04 BCL11B 1.008 2.011 3.290E-08 3.460E-06 LTBP3 1.010 2.013 2.205E-03 2.792E-02 MTFP1 1.012 2.017 3.627E-03 3.971E-02 NDUFAF5 1.014 2.019 1.061E-03 1.633E-02 RORA 1.023 2.033 2.218E-04 5.237E-03 TWF1 1.027 2.037 1.270E-08 1.500E-06 SYCP2 1.029 2.040 1.876E-03 2.471E-02 ENSG00000257497 1.029 2.041 1.512E-03 2.118E-02 RNF139 1.029 2.041 3.700E-05 1.309E-03 NR4A1 1.030 2.042 1.180E-05 5.299E-04 DHRS3 1.035 2.049 2.316E-03 2.886E-02 ENSG00000274460 1.037 2.052 2.306E-03 2.876E-02 NDST2 1.038 2.054 3.160E-03 3.592E-02 SHLD3 1.040 2.057 6.730E-05 2.057E-03 SPEG 1.041 2.058 2.326E-03 2.894E-02 ENSG00000255182 1.045 2.063 1.194E-04 3.237E-03 SNHG15 1.048 2.068 7.240E-11 1.700E-08 MIR22HG 1.052 2.074 2.105E-04 5.024E-03 ACTA2-AS1 1.054 2.076 3.290E-03 3.689E-02 ENSG00000223511 1.063 2.089 4.530E-05 1.530E-03 TSPYL2 1.064 2.090 2.260E-09 3.250E-07 SEC14L2 1.069 2.098 1.593E-04 4.010E-03 TUBB2A 1.071 2.102 5.035E-03 4.938E-02 NAF1 1.072 2.103 5.360E-06 2.746E-04 NCR3LG1 1.074 2.105 2.084E-03 2.673E-02 ENSG00000265625 1.079 2.113 4.492E-03 4.577E-02 PGGHG 1.083 2.119 5.427E-04 9.893E-03 WHAMM 1.083 2.119 8.080E-06 3.835E-04 PRR7 1.084 2.120 1.139E-03 1.725E-02 IKZF5 1.084 2.120 5.300E-13 2.050E-10 ENSG00000260404 1.085 2.122 3.780E-06 2.072E-04 CD69 1.085 2.122 9.960E-09 1.230E-06 ITPRIP 1.088 2.126 3.590E-08 3.720E-06 IER3 1.090 2.129 3.788E-03 4.074E-02 C6orf226 1.090 2.129 7.808E-04 1.300E-02 FAM86B3P 1.095 2.135 1.933E-03 2.527E-02 ADGRB1 1.101 2.145 2.540E-03 3.100E-02 NA 1.104 2.149 3.240E-04 6.815E-03 RBM34 1.105 2.150 3.665E-03 3.999E-02 AFAP1 1.105 2.151 3.408E-03 3.785E-02 LINC01089 1.111 2.159 5.620E-06 2.838E-04 ENSG00000269951 1.120 2.174 4.229E-03 4.389E-02 EML5 1.123 2.177 4.451E-03 4.550E-02 PASK 1.127 2.183 1.010E-05 4.609E-04 ARRDC3 1.133 2.193 4.308E-04 8.445E-03 TOE1 1.133 2.194 1.010E-11 2.960E-09 RBM38 1.137 2.199 6.240E-07 4.480E-05 PIGA 1.144 2.210 1.900E-06 1.160E-04 ENSG00000258944 1.146 2.213 2.697E-04 5.994E-03 TRBV30 1.147 2.214 1.401E-03 2.012E-02 YOD1 1.155 2.227 7.340E-11 1.700E-08 ENSG00000255026 1.160 2.235 7.886E-04 1.306E-02 OSER1 1.162 2.238 6.670E-18 5.550E-15 IGLV6-57 1.163 2.239 1.796E-03 2.396E-02 CCDC59 1.164 2.240 2.610E-08 2.800E-06 CHASERR 1.169 2.249 5.680E-12 1.750E-09 LINC00653 1.169 2.249 5.070E-06 2.633E-04 SIAH1 1.173 2.254 3.080E-07 2.510E-05 BEX2 1.179 2.264 7.620E-09 9.910E-07 CLN8-AS1 1.180 2.266 2.719E-03 3.246E-02 ENSG00000273253 1.183 2.270 4.109E-04 8.147E-03 LZTS3 1.183 2.271 3.970E-05 1.381E-03 DDX47 1.184 2.272 1.040E-09 1.690E-07 TENT5C 1.186 2.275 2.070E-07 1.850E-05 EIF4A1 1.186 2.275 5.590E-10 9.810E-08 CACNA1H 1.187 2.276 5.840E-05 1.867E-03 CLP1 1.190 2.282 3.870E-07 3.010E-05 DUSP10 1.192 2.285 6.390E-06 3.131E-04 CDKN1B 1.196 2.291 2.230E-08 2.450E-06 ZBTB21 1.204 2.303 5.340E-09 7.110E-07 DUS3L 1.206 2.307 1.670E-07 1.520E-05 NAP1L5 1.211 2.315 1.250E-04 3.353E-03 SLC7A5 1.219 2.328 1.430E-07 1.330E-05 SIK1B 1.222 2.333 3.780E-06 2.072E-04 ERFL 1.223 2.334 4.521E-04 8.652E-03 SNORD4A 1.232 2.349 1.780E-03 2.376E-02 CBX4 1.232 2.349 1.650E-12 5.500E-10 JUNB 1.234 2.352 1.660E-06 1.031E-04 C1R 1.239 2.360 2.424E-03 2.982E-02 ADAMTS7P1 1.240 2.362 1.664E-03 2.271E-02 CXCR4 1.249 2.376 2.900E-13 1.240E-10 RBM38-AS1 1.250 2.378 1.902E-03 2.497E-02 CSRNP1 1.250 2.379 3.480E-12 1.090E-09 PTP4A1 1.255 2.387 2.170E-08 2.400E-06 SPATA2 1.257 2.391 1.080E-08 1.330E-06 ZNF551 1.259 2.392 2.350E-10 4.960E-08 ZNF367 1.263 2.399 5.340E-05 1.737E-03 HBEGF 1.268 2.408 7.978E-04 1.317E-02 DNAJB1 1.270 2.411 9.110E-19 8.930E-16 ENSG00000280138 1.273 2.417 5.040E-19 5.250E-16 ARRDC4 1.278 2.425 1.640E-06 1.019E-04 PELI1 1.282 2.431 5.520E-10 9.790E-08 CTSF 1.286 2.438 2.097E-04 5.021E-03 RNF103 1.294 2.452 1.670E-08 1.870E-06 BNC2 1.298 2.460 4.575E-03 4.625E-02 VEGFA 1.299 2.461 1.303E-03 1.907E-02 POLR1F 1.305 2.471 8.340E-14 4.020E-11 SOX4 1.306 2.472 9.710E-09 1.210E-06 HIF1A 1.307 2.475 4.400E-10 8.050E-08 ENSG00000224505 1.308 2.477 1.838E-03 2.436E-02 JUND 1.313 2.484 9.570E-09 1.200E-06 FOSB 1.313 2.485 6.710E-11 1.620E-08 MIR590 1.314 2.486 1.505E-03 2.114E-02 NR3C2 1.325 2.505 4.103E-03 4.302E-02 PLK3 1.325 2.505 1.350E-09 2.100E-07 IL12A 1.325 2.506 3.290E-03 3.689E-02 SNHG9 1.329 2.511 8.253E-04 1.346E-02 COL18A1 1.340 2.531 1.042E-03 1.610E-02 ZNF331 1.340 2.531 1.390E-06 8.870E-05 ADAMTS17 1.346 2.542 1.707E-04 4.253E-03 RPS6KL1 1.348 2.546 1.230E-03 1.824E-02 TAS1R3 1.350 2.549 2.310E-06 1.354E-04 IL23A 1.359 2.565 3.190E-05 1.165E-03 ENSG00000233264 1.360 2.567 7.080E-05 2.121E-03 C17orf49 1.364 2.574 8.500E-09 1.080E-06 PTCH1 1.367 2.580 4.969E-03 4.889E-02 ENSG00000256152 1.385 2.612 2.891E-04 6.312E-03 ZNF394 1.392 2.625 4.330E-13 1.760E-10 HDGFL3 1.397 2.634 4.760E-05 1.584E-03 LINC02390 1.404 2.646 1.660E-05 6.972E-04 SBDSP1 1.409 2.655 8.210E-21 1.140E-17 SLC2A3 1.410 2.657 2.500E-07 2.110E-05 PFKFB3 1.412 2.661 3.230E-11 8.030E-09 NTN5 1.413 2.662 1.366E-03 1.974E-02 NSG1 1.421 2.678 5.188E-04 9.551E-03 SBDS 1.425 2.685 6.640E-13 2.510E-10 SOCS3 1.428 2.691 4.960E-06 2.588E-04 DDIT3 1.435 2.703 3.840E-16 2.560E-13 ZNF14 1.457 2.744 7.420E-10 1.210E-07 FBXO33 1.457 2.744 5.270E-20 6.270E-17 OTUD7A 1.460 2.750 1.040E-06 6.980E-05 DFFBP1 1.464 2.758 2.560E-05 9.866E-04 SDE2 1.464 2.759 1.150E-17 8.730E-15 PDE4D 1.468 2.766 4.040E-09 5.600E-07 CTLA4 1.481 2.791 9.951E-04 1.557E-02 RN7SL2 1.481 2.792 1.260E-05 5.585E-04 EIF2AK3-DT 1.482 2.793 1.190E-08 1.430E-06 FOSL2 1.487 2.804 4.440E-17 3.220E-14 SNORA75 1.491 2.812 2.518E-03 3.082E-02 CITED4 1.494 2.816 2.000E-05 8.122E-04 NDUFV2 1.496 2.820 8.150E-12 2.420E-09 PIM3 1.500 2.829 9.130E-29 5.070E-25 IGLV4-60 1.507 2.843 3.758E-03 4.050E-02 GADD45A 1.519 2.866 2.780E-10 5.590E-08 ENSG00000229299 1.519 2.867 6.000E-06 2.991E-04 B3GNT7 1.524 2.876 7.980E-07 5.560E-05 EGR1 1.538 2.905 9.542E-04 1.514E-02 ENSG00000279520 1.540 2.907 2.340E-09 3.340E-07 RAB3A 1.541 2.910 1.948E-03 2.540E-02 LINC02033 1.542 2.912 4.793E-03 4.757E-02 ENSG00000275056 1.546 2.921 1.135E-03 1.721E-02 ENSG00000228201 1.553 2.935 5.026E-04 9.348E-03 RSPH4A 1.560 2.948 4.216E-03 4.382E-02 HAR1A 1.562 2.954 7.110E-04 1.209E-02 NFKBIA 1.571 2.971 1.490E-09 2.300E-07 FGFR1 1.573 2.976 1.040E-06 6.980E-05 WDR86 1.578 2.986 9.610E-06 4.400E-04 SCARF2 1.580 2.989 3.076E-03 3.537E-02 JUN 1.589 3.008 1.260E-21 2.090E-18 CEROX1 1.593 3.016 4.580E-07 3.470E-05 RPL13P12 1.596 3.023 1.579E-04 3.997E-03 ENSG00000260708 1.596 3.023 2.880E-12 9.230E-10 BCL3 1.613 3.060 1.080E-09 1.720E-07 MMP28 1.618 3.071 7.460E-04 1.254E-02 LINC00304 1.630 3.096 3.968E-04 7.966E-03 MYRF 1.634 3.103 8.451E-04 1.370E-02 ENSG00000276517 1.640 3.117 8.122E-04 1.333E-02 TNRC18P1 1.649 3.137 1.341E-04 3.513E-03 FAM183BP 1.650 3.138 1.392E-03 2.004E-02 IRS2 1.653 3.144 1.170E-09 1.840E-07 TRPM5 1.690 3.227 3.522E-03 3.881E-02 ENSG00000276853 1.695 3.238 2.018E-03 2.612E-02 MTSS2 1.697 3.243 9.540E-11 2.150E-08 RBKS 1.719 3.292 1.027E-03 1.591E-02 ENSG00000255847 1.723 3.301 3.640E-13 1.520E-10 ENSG00000273306 1.752 3.367 1.572E-04 3.991E-03 ENC1 1.759 3.384 3.320E-07 2.670E-05 ENSG00000279908 1.775 3.423 2.420E-09 3.410E-07 FAM153A 1.799 3.480 6.660E-05 2.041E-03 ENSG00000232891 1.804 3.492 4.911E-04 9.204E-03 BTG3 1.827 3.547 1.400E-11 3.880E-09 ZBTB10 1.829 3.552 2.450E-26 5.830E-23 KCNK7 1.835 3.568 9.350E-06 4.291E-04 ZC3H12A 1.840 3.580 9.790E-28 4.080E-24 EGR2 1.848 3.599 1.150E-05 5.160E-04 KLF5 1.849 3.601 1.630E-05 6.907E-04 TNFAIP3 1.853 3.612 1.110E-08 1.340E-06 ENSG00000279765 1.859 3.627 7.840E-05 2.309E-03 CCL3L3 1.886 3.696 3.710E-05 1.310E-03 CFL2 1.895 3.719 1.500E-12 5.090E-10 TTC34 1.896 3.721 1.450E-05 6.245E-04 CRABP2 1.915 3.771 1.857E-03 2.455E-02 TP53INP2 1.918 3.778 1.310E-15 7.510E-13 UPK3B 1.928 3.805 1.020E-06 6.930E-05 RGS17P1 1.929 3.808 3.560E-05 1.267E-03 LMTK3 1.930 3.811 3.880E-07 3.010E-05 KRT18 1.933 3.820 6.919E-04 1.184E-02 PSMD10P1 1.980 3.944 2.660E-07 2.230E-05 OSM 1.982 3.952 3.330E-05 1.202E-03 DUSP2 2.021 4.060 3.140E-11 7.920E-09 ENSG00000261159 2.031 4.086 1.614E-03 2.228E-02 NA 2.035 4.099 4.230E-05 1.447E-03 MAFF 2.085 4.242 1.260E-08 1.500E-06 LRRC32 2.090 4.256 7.562E-04 1.266E-02 RHBDL1 2.123 4.357 1.977E-04 4.799E-03 SNAI1 2.148 4.432 9.033E-04 1.444E-02 AREG 2.166 4.489 4.989E-04 9.308E-03 ENSG00000272256 2.171 4.504 1.440E-05 6.211E-04 ENSG00000267655 2.203 4.603 1.972E-03 2.567E-02 FAM153B 2.206 4.614 3.677E-04 7.499E-03 RND1 2.213 4.635 7.490E-04 1.258E-02 RPL23AP81 2.261 4.794 4.746E-04 8.955E-03 FFAR1 2.265 4.806 3.720E-18 3.440E-15 NA 2.267 4.812 2.350E-10 4.960E-08 ENSG00000245869 2.314 4.971 5.380E-06 2.748E-04 DIP2A-IT1 2.339 5.059 1.960E-06 1.186E-04 MATN1 2.339 5.061 3.210E-05 1.169E-03 ENSG00000231305 2.357 5.122 7.635E-04 1.275E-02 ENSG00000256712 2.367 5.157 2.747E-03 3.269E-02 GRM2 2.392 5.248 5.290E-09 7.110E-07 MIR4420 2.399 5.274 2.860E-06 1.639E-04 CXCL8 2.400 5.279 7.380E-10 1.210E-07 ENSG00000207525 2.410 5.316 3.989E-04 7.997E-03 RBBP4P1 2.416 5.336 3.657E-03 3.995E-02 SULT1A2 2.435 5.406 9.660E-07 6.570E-05 TCTE1 2.442 5.433 5.029E-03 4.935E-02 AVPI1 2.443 5.440 8.720E-05 2.508E-03 HLA-U 2.444 5.440 1.685E-03 2.288E-02 ENSG00000275927 2.458 5.494 1.932E-03 2.527E-02 EREG 2.501 5.660 5.270E-05 1.724E-03 LOC105378721 2.524 5.750 6.651E-04 1.153E-02 TNFSF9 2.532 5.785 8.500E-05 2.459E-03 FLT4 2.538 5.807 6.380E-05 1.973E-03 CHMP4BP1 2.538 5.808 6.960E-05 2.100E-03 DUSP4 2.605 6.083 3.700E-06 2.048E-04 ENSG00000274677 2.653 6.288 3.481E-04 7.214E-03 ENSG00000278022 2.676 6.390 4.150E-05 1.425E-03 ENSG00000256913 2.717 6.576 4.902E-04 9.198E-03 NR4A3 2.718 6.580 1.740E-07 1.570E-05 PER1 2.758 6.765 6.470E-21 9.800E-18 TAMALIN 2.791 6.921 3.640E-45 6.070E-41 CD83 2.850 7.210 2.750E-24 5.100E-21 FAM238A 2.902 7.473 2.770E-16 1.920E-13 ADRB1 2.906 7.496 2.030E-05 8.221E-04 DUSP8 2.981 7.895 8.650E-06 4.024E-04 THNSL2 3.049 8.277 3.100E-03 3.557E-02 ENSG00000270681 3.108 8.624 3.192E-04 6.754E-03 ACTN1-AS1 3.126 8.732 4.670E-06 2.452E-04 FOSL1 3.150 8.877 4.726E-03 4.716E-02 TPBGL 3.156 8.914 4.160E-03 4.334E-02 CHRM4 3.189 9.120 2.280E-06 1.340E-04 TMEM119 3.276 9.684 1.179E-03 1.772E-02 NR4A2 3.339 10.116 7.350E-18 5.830E-15 GRK5-IT1 3.339 10.117 1.958E-04 4.771E-03 MMP9 3.528 11.532 8.140E-06 3.841E-04 GEM 3.551 11.718 4.821E-03 4.776E-02 G0S2 3.560 11.793 6.010E-16 3.850E-13 SAXO2 3.803 13.956 6.210E-26 1.290E-22 HAR1B 3.908 15.007 5.480E-05 1.775E-03 ABHD17AP6 3.928 15.221 3.253E-03 3.665E-02 ENSG00000259635 4.089 17.022 4.475E-04 8.610E-03 IL13 4.111 17.283 2.698E-04 5.994E-03 SLED1 4.143 17.665 3.646E-03 3.986E-02 TEX45 5.004 32.082 4.948E-04 9.244E-03 YAP1P1 5.831 56.906 3.275E-04 6.864E-03 CLLU1-AS1 5.963 62.401 9.653E-04 1.527E-02 ENSG00000224029 6.334 80.649 4.380E-05 1.492E-03 RPS4XP22 6.439 86.769 2.270E-03 2.851E-02 LRRC7 6.948 123.489 1.091E-04 3.014E-03 RASD2 6.974 125.745 2.660E-05 1.008E-03 TUBB8B 6.974 125.745 2.660E-05 1.008E-03 MTCO3P12 8.403 338.535 1.370E-05 5.963E-04 ZFP57 8.785 441.159 2.190E-09 3.180E-07 [93]Open in a new tab Patients with AD and HCs were stratified by age (0‒6 months and 7‒12 months), and differential expression analysis on RNA-seq data was performed between the four groups: children with AD aged >6 months above versus age-matched HCs, children with AD aged <6 months versus age-matched HCs, patients with AD aged >6 months versus patients with AD aged <6 months, and HCs aged >6 months versus HCs aged <6 months. Meeting criteria were set at FC ≥1.5 and FDR <0.05. Abbreviations: AD, atopic dermatitis; FC, fold change; FDR, false discovery rate; HC, healthy control; KLK, kallikrein; MMP, matrix metalloproteinase; RNA-seq, RNA sequencing; STAT, signal transducer and activator of transcription; TLR, toll-like receptor. Table 4. Effect of Infant’s Age on Validated DEG in Infants with AD DEG Group LFC FC FDR IL18RAP Patients with AD aged >6 mo versus HCs ‒1.968 0.256 0.003 Patients with AD aged <6 mo versus HCs ‒1.309 0.404 0.043 IL1B Patients with AD aged <6 mo versus HCs 3.901 14.942 0.000 TNF Patients with AD aged <6 mo versus HCs 3.092 8.526 0.000 TREM1 Patients with AD aged <6 mo versus HCs 3.164 8.963 0.000 EGR3 Patients with AD aged <6 mo versus HCs 5.076 33.732 0.015 [94]Open in a new tab Shown is the effect of infant’s age on the expression of selected genes that were differentially expressed in infants with AD and validated by RT-qPCR. Differential expression analysis between patients with AD and HCs was performed using DESeq2 on RNA-seq data after stratifying the dataset by age (0‒6 months and 7‒12 months). Abbreviations: AD, atopic dermatitis; AIF, apoptosis-inducing factor; DEG, differentially expressed gene; FC, fold change; FDR, false discovery rate; HC, healthy control; LFC, log[2] fold change; OSM, oncostatin M; RNA-seq, RNA sequencing; XAF1, XIAP-associated factor 1. Figure 3. [95]Figure 3 [96]Open in a new tab Effect of infant’s age on the expression of differentially expressed genes in infants with AD. RT-qPCR analyses for five genes from the top 10 differentially expressed genes identified by high-throughput RNA sequencing: (a) IL18RAP, (b) IL1β, (c) TNF, (d) TREM1, and (e) EGR3 in children with AD (n = 27) and healthy controls (n = 17) after stratifying the dataset by age (0‒6 months and 7‒12 months). Fold change was calculated by 2-ΔΔCT method. The normalized expression data were log[2] transformed and shown as the means ± SD. Significant difference among groups was calculated by unpaired t test with Welch’s correction for normal distribution or with Mann‒Whitney rank-sum test for non-normal distribution data. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001. AD, atopic dermatitis; HC, healthy control. Gene ontology and pathway analysis of DEGs To gain insight into the gene ontology (GO) categories of DEGs between the AD group and control group, all DEGs were uploaded to the DAVID (Database for Annotation, Visualization and Integrated Discovery) database. GO analysis contained three categories: biological process (BP), cellular component (CC), and molecular function (MF). In total, 86 significant GO terms were enriched for DEGs identified in the AD group, of which 57 were within the BP category, 21 were within the CC category, and 8 were within the MF category. The enriched BP categories included immune response, inflammatory response, regulation of immune response, leukocyte migration, positive regulation of NF-kB transcription factor activity, cell adhesion, cell surface receptor signaling pathway, and many others. In the category CC, the DEGs were significantly enriched in the plasma membrane, extracellular region, extracellular exosome, cell surface, and cytoplasm. Furthermore, in the category MF, DEGs were mainly enriched in antigen binding, receptor activity, cytokine activity, enzyme binding, and protein binding. The selected pathways significantly enriched in the AD group included hematopoietic cell lineage, NK cell‒mediated cytotoxicity, phosphoinositide 3-kinase‒protein kinase B signaling pathway, cytokine‒cytokine receptor interaction, extracellular matrix‒receptor interaction, and immunoregulatory interactions between a lymphoid and a nonlymphoid cell ([97]Figure 4a and b). Further details of the results of the GO enrichment and pathway analyses are provided in [98]Table 5. Figure 4. [99]Figure 4 [100]Open in a new tab GO enrichment and pathway analysis of differentially expressed genes. (a) The top 20 enriched GO terms; the x-axis represents gene counts, and the y-axis represents GO terms. (b) Selected KEGG pathways; the x-axis represents gene counts, and the y-axis represents KEGG pathway names. Akt, protein kinase B; ECM, extracellular matrix; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PI3K, phosphoinositide 3-kinase. Table 5. GO Enrichment and Pathway Analyses of Differentially Expressed Genes GO Term Gene Count P-Value Genes Biological process Regulation of immune response 17 3.76E-12 ICAM1, IGLV1-44, IGKV5-2, NCR1, IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV2-23, IGKV4-1, KLRF1,TREM1, KIR2DL3, TREML1, IGLC2, KLRD1, and IGKV3-15 Receptor-mediated endocytosis 16 8.68E-11 LDLR, IGLV1-44, IGKV5-2, JCHAIN, SPARC, IGLV2-11, IGLV2-8, IGLV3-19, CTTN, IGKV1-5, IGLV2-23, IGKV4-1, IGLC2, LRP3, CD14, and IGKV3-15 Complement activation 11 4.37E-09 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, CLU, IGKV4-1, IGLC2, and IGKV3-15 Immune response 20 4.97E-09 IL18R1, TNF, IL18RAP, CXCL5, IGLV1-44, IGKV5-2, JCHAIN, FASLG, PF4, IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, PPBP, FCAR, IGLV2-23, IGKV4-1, IL1B, KIR2DL3, and IGKV3-15 Complement activation and classical pathway 11 1.56E-08 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, CLU, IGKV4-1, IGLC2, and IGKV3-15 Platelet activation 10 7.55E-07 VWF, GP6, F5, C6ORF25, PF4, GP1BA, ITGB3, TREML1, CLEC1B, and GP9 Fc-γ receptor signaling pathway involved in phagocytosis 10 1.74E-06 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Platelet degranulation 9 3.36E-06 VWF, APP, F5, PPBP, CLU, PF4, SPARC, ITGB3, and ITGA2B Blood coagulation 11 5.08E-06 PRKAR2B, VWF, GP6, F5, C6ORF25, PDGFC, GP1BA, PDGFD, ITGB3, GP9, and PLAUR FCERI signaling pathway 10 2.71E-05 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Positive regulation of nitric oxide biosynthetic process 6 3.54E-05 ICAM1, TNF, CLU, IL1B, PTX3, and KLF4 Proteolysis 14 0.000 NRIP3, IGLV1-44, IGKV5-2, ANPEP, MMP25, IGLV2-11, IGKV1-5, IGLV3-19, IGLV2-8, F5, IGLV2-23, IGKV4-1, IGLC2, and IGKV3-15 Inflammatory response 12 0.001 SDC1, TNF, IL18RAP, PPBP, CXCL5, ANXA1, IL1B, PF4, PTX3, NLRP3, CD14, and MMP25 Antibacterial humoral response 5 0.001 APP, ADM, HIST2H2BE, HIST1H2BJ, and JCHAIN Positive regulation of cell division 5 0.001 TAL1, PPBP, IL1B, PDGFC, and PDGFD Innate immune response 12 0.001 APP, CLU, ANXA1, JCHAIN, PADI4, TREM1, PTX3, NLRP3, IGLC2, TREML1, KLRD1, and CD14 ECM organization 8 0.002 ICAM1, VWF, APP, TNF, ITGB5, SPARC, ITGB3, and ITGA2B Response to glucocorticoid 5 0.003 SDC1, TNF, ADM, SPARC, and ADAM9 Response to lipopolysaccharide 7 0.003 PPBP, ADM, CXCL5, FASLG, PF4, SPARC, and TRIB1 Positive regulation of chemokine biosynthetic process 3 0.003 EGR1, TNF, and IL1B Negative regulation of extrinsic apoptotic signaling pathway in absence of ligand 4 0.004 TNF, MCL1, IL1B, and PF4 Viral entry into host cell 5 0.005 ICAM1, LDLR, ITGB5, ANPEP, and ITGB3 Response to yeast 3 0.006 APP, ADM, and PTX3 Defense response to Gram-positive bacterium 5 0.007 APP, TNF, ADM, HIST2H2BE, and HIST1H2BJ Negative regulation of gene expression 6 0.007 TNF, LDLR, GAS2L1, ZNF503, MYADM, and KLF4 Cell adhesion mediated by integrin 3 0.007 ICAM1, ITGB3, and ADAM9 Positive regulation of membrane protein ectodomain proteolysis 3 0.007 TNF, IL1B, and ADAM9 Positive regulation of IFN-γ production 4 0.008 IL18R1, TNF, IL1B, and CD14 Cell surface receptor signaling pathway 8 0.01 IL18RAP, ANXA1, GP1BA, TSPAN9, KLRF1, KLRD1, CD14, and CLEC1B Blood coagulation, intrinsic pathway 3 0.011 VWF, GP1BA, and GP9 Positive regulation of leukocyte chemotaxis 3 0.011 PPBP, CXCL5, and PF4 Integrin-mediated signaling pathway 5 0.011 C6ORF25, ITGB5, ITGB3, ADAM9, and ITGA2B Platelet formation 3 0.012 TAL1, C6ORF25, and CLEC1B Positive regulation of transcription from RNA polymerase II promoter 17 0.012 EGR1, NAMPT, TNF, EGR2, ABLIM3, PF4, MYBL1, NLRP3, AHR, TAL1, APP, SPX, BHLHA15, IL1B, MAML3, FOSL1, and KLF4 Cellular response to hydrogen peroxide 4 0.014 IL18RAP, ANXA1, PDGFD, and KLF4 Positive regulation of NF-kB import into the nucleus 3 0.014 IL18R1, TNF, and IL1B Positive regulation of MAPK activity 4 0.015 TNF, PDE5A, PDGFC, and PDGFD Positive regulation of smooth muscle cell proliferation 4 0.016 NAMPT, TNF, PDGFD, and ALOX12 Cellular response to lipopolysaccharide 5 0.017 ICAM1, TNF, NLRP3, CD14, and ADAM9 Regulation of gastric acid secretion 2 0.017 SGK1 and KCNQ1 Cell adhesion 10 0.02 ICAM1, VWF, APP, SCN1B, ITGB5, GP1BA, ITGB3, ADAM9, GP9, and ITGA2B Leukocyte migration 5 0.022 ICAM1, GP6, ESAM, TREM1, and ITGB3 Regulation of cell proliferation 6 0.024 TAL1, SGK1, TNF, PPBP, ANXA1, and PF4 Establishment or maintenance of microtubule cytoskeleton polarity 2 0.026 KIF2C and LMNA positive regulation of calcidiol 1-monooxygenase activity 2 0.026 TNF and IL1B Positive regulation of phagocytosis 3 0.026 TNF, IL1B, and PTX3 Positive regulation of gene expression 7 0.028 TNF, LDLR, ID1, IL1B, PF4, KLF4, and ALOX12 Positive regulation of NF-kB transcription factor activity 5 0.03 ICAM1, TNF, CLU, IL1B, and NLRP3 Lipopolysaccharide-mediated signaling pathway 3 0.032 TNF, IL1B, and CD14 Sequestering of triglyceride 2 0.035 TNF and IL1B IL-1 beta production 2 0.043 IL1B and NLRP3 Positive regulation of fever generation 2 0.043 TNF and IL1B Cell matrix adhesion 4 0.044 ITGB5, ITGB3, ADAM9, and ITGA2B TGFβ receptor signaling pathway 4 0.047 ID1, CLDN5, ITGB5, and ADAM9 Positive regulation of cysteine-type endopeptidase activity involved in apoptotic process 3 0.048 TNF, NLRP3, and ALOX12 Positive regulation of apoptotic process 7 0.049 TNF, ADM, CLU, FASLG, FOSL1, MELK, and DUSP6 Platelet aggregation 3 0.049 GP1BA, ITGB3, and ITGA2B Cellular component Plasma membrane 68 4.45E-09 SEPT5, IGLV1-44, LDLR, C6ORF25, CLDN5, FASLG, IGKV1-12, TSPAN9, MMP25, GLDC, GP9, ATP2B1, PRKAR2B, CTTN, APP, GP6, HOMER3, IGLV2-23, ZNF185, DLG3, PDGFC, ESAM, FAM129B, KLRD1, KCNQ1, ICAM1, SGK1, IL18RAP, SLCO4A1, WLS, NCR1, MYADM, PLAUR, IGLV2-11, IGKV1-5, SDC1, F5, COLQ, IGKV4-1, TREM1, KIR2DL3, EMP1, MELK, CLEC1B, ITGA2B, TNF, SCN1B, CALD1, IGKV5-2, ITGB5, GNG11, ITGB3, C2ORF88, IGLV2-8, IGLV3-19, GP1BA, KLRF1, IGKV3-15, IL18R1, ANXA1, SPARC, RAPH1, AQP10, FCAR, CPNE2, IGLC2, TREML1, and CD14 Extracellular region 34 1.16E-06 LTBP1, SCN1B, TNF, IGLV1-44, CXCL5, IGKV5-2, CLU, JCHAIN, FASLG, PF4, IGKV1-12, IGLV2-8, APP, IGLV3-19, IGLV2-23, IL1B, PDGFC, PDGFD, PTX3, IGKV3-15, ANXA1, SPARC, NLRP3, IGLV2-11, VWF, IGKV1-5, F5, ADM, FCAR, PPBP, IGKV4-1, TREM1, IGLC2, and CD14 Extracellular space 30 2.25E-06 NAMPT, TNF, CXCL5, FAM20C, CLU, JCHAIN, FASLG, PF4, ANPEP, APP, SPX, HIST1H2BJ, IL1B, DLG3, PDGFC, PDGFD, PTX3, ADAM9, ICAM1, ANXA1, SPARC, F5, PPBP, ADM, COLQ, HIST2H2BE, FRMD4B, IGLC2, CD14, and CMTM5 Platelet alpha granule lumen 7 6.55E-06 VWF, APP, F5, PPBP, CLU, PF4, and SPARC Cell surface 17 1.34E-05 ICAM1, TNF, LDLR, CLU, ANXA1, ITGB5, SPARC, and ITGB3, APP, SDC1, GP6, GP1BA, PDGFC, TREML1, INTU, ITGA2B, and ADAM9 Extracellular exosome 44 4.28E-05 HIST1H2AC, NAMPT, CLU, FAM20C, CLDN5, JCHAIN, FASLG, ITGB5, ANPEP, ITGB3, ATP2B1, PRKAR2B, CTTN, APP, IGLV3-19, GP6, PGRMC1, IL1B, PDGFC, ESAM, GP1BA, FAM129B, PDGFD, TUBA1A, TUBB1, ADAM9, ICAM1, ANXA1, WLS, MYADM, PLAUR, IGLV2-11, PDZK1IP1, VWF, IGKV1-5, SDC1, HIST2H2BE, SH3BGRL2, CPNE2, IGLC2, CD14, XYLB, ALOX12, and ITGA2B Membrane raft 9 3.55E-04 ATP2B1, PRKAR2B, ICAM1, APP, TNF, SDPR, KCNQ1, MYADM, and CD14 External side of the plasma membrane 9 4.43E-04 ICAM1, SDC1, TNF, LDLR, FASLG, ANPEP, IGLC2, KLRD1, and ITGA2B Focal adhesion 11 0.002 ICAM1, SDC1, CTTN, ZNF185, ANXA1, ITGB5, TSPAN9, ITGB3, ADAM9, PLAUR, and ITGA2B Blood microparticle 7 0.002 IGKV1-5, CLU, JCHAIN, IGKV4-1, IGLC2, IGKV3-15, and ITGA2B Platelet alpha granule membrane 3 0.005 SPARC, ITGB3, and ITGA2B Platelet alpha granule 3 0.006 VWF, SPARC, and TREML1 Integral component of the plasma membrane 22 0.008 ICAM1, TNF, LDLR, SLCO4A1, FASLG, ANPEP, TSPAN9, ITGB3, NCR1, AQP10, PLAUR, GP9, ATP2B1, APP, SDC1, GP6, FCAR, GP1BA, KLRF1, KIR2DL3, CLEC1B, and ITGA2B Phagocytic cup 3 0.011 TNF, PEAR1, and ANXA1 Clathrin-coated pit 4 0.011 APP, CTTN, LDLR, and LRP3 Anchored component of the external side of the plasma membrane 3 0.014 GGTA1P, GP1BA, and CD14 Basolateral plasma membrane 6 0.018 ATP2B1, LDLR, ANXA1, DLG3, KCNQ1, and ADAM9 Integrin complex 3 0.021 ITGB5, ITGB3, and ITGA2B Receptor complex 5 0.022 APP, LDLR, ITGB5, ITGB3, and KLRD1 Dendritic shaft 3 0.029 PRKAR2B, APP, and DLG3 Cytoplasm 55 0.043 NAMPT, MCM10, ISG20, PRKAR2B, CTTN, APP, HOMER3, SDPR, ZNF185, HIST1H2BJ, DLG3, PIWIL2, PDGFC, FAM129B, TUBB1, KCNQ1, EGR1, SGK1, EGR2, PADI4, UBE2C, NLRP3, AHR, SH2D2A, SDC1, ADM, HIST2H2BE, FRMD4B, PPP1R15A, INTU, XYLB, ALOX12, MCL1, ABLIM3, CLU, TRIB1, SPATS2, NCAPG, RNF165, STRIP2, SKA3, GP1BA, HRASLS2, ANXA1, LMNA, CDC20, SPARC, RAPH1, SH3BGRL2, GAS2L1, CPNE2, RFX2, TREML1, KLF4, and DUSP6 Molecular function Antigen binding 12 1.30E-09 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, JCHAIN, IGKV4-1, KIR2DL3, IGLC2, and IGKV3-15 Receptor activity 11 1.82E-05 ICAM1, IL18R1, GP6, IL18RAP, LDLR, ITGB5, ANPEP, TREM1, ITGB3, KIR2DL3, and PLAUR Serine-type endopeptidase activity 11 7.17E-05 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, F5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Virus receptor activity 5 0.003 ICAM1, LDLR, ITGB5, ANPEP, and ITGB3 Platelet-derived GF receptor binding 3 0.007 PDGFC, PDGFD, and ITGB3 Collagen binding 4 0.015 VWF, GP6, SPARC, and ADAM9 ECM binding 3 0.021 SPARC, ITGB3, and ITGA2B IgA binding 2 0.026 FCAR and JCHAIN Pathway KEGG pathway ECM‒receptor interaction 8 4.38E-05 VWF, SDC1, GP6, ITGB5, GP1BA, ITGB3, GP9, and ITGA2B Hematopoietic cell lineage 8 4.38E-05 TNF, IL1B, ANPEP, GP1BA, ITGB3, CD14, GP9, and ITGA2B African trypanosomiasis 4 0.006 ICAM1, TNF, IL1B, and FASLG Pertussis 5 0.009 TNF, CXCL5, IL1B, NLRP3, and CD14 Hypertrophic cardiomyopathy 5 0.011 TNF, LMNA, ITGB5, ITGB3, and ITGA2B NK cell‒mediated cytotoxicity 6 0.011 ICAM1, TNF, FASLG, KIR2DL3, NCR1, and KLRD1 PI3K‒Akt signaling pathway 10 0.013 VWF, SGK1, MCL1, ITGB5, FASLG, GNG11, PDGFC, PDGFD, ITGB3, and ITGA2B Dilated cardiomyopathy 5 0.014 TNF, LMNA, ITGB5, ITGB3, and ITGA2B Platelet activation 6 0.014 VWF, GP6, GP1BA, ITGB3, GP9, and ITGA2B Malaria 4 0.017 ICAM1, SDC1, TNF, and IL1B Cytokine‒cytokine receptor interaction 8 0.017 IL18R1, TNF, IL18RAP, PPBP, CXCL5, IL1B, FASLG, and PF4 Pathogenic E. coli infection 4 0.018 CTTN, TUBB1, TUBA1A, and CD14 Proteoglycans in cancer 7 0.023 SDC1, CTTN, TNF, ITGB5, FASLG, ITGB3, and PLAUR Phagosome 6 0.025 FCAR, ITGB5, ITGB3, TUBB1, TUBA1A, and CD14 Inflammatory bowel disease 4 0.033 IL18R1, TNF, IL18RAP, and IL1B Arrhythmogenic right ventricular cardiomyopathy 4 0.037 LMNA, ITGB5, ITGB3, and ITGA2B Reactome pathway Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell 17 2.07E-10 ICAM1, IGLV1-44, IGKV5-2, NCR1, IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV2-23, IGKV4-1, KLRF1, TREM1, KIR2DL3, TREML1, IGLC2, KLRD1, and IGKV3-15 Scavenging of heme from plasma 11 4.03E-09 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, JCHAIN, IGKV4-1, IGLC2, and IGKV3-15 CD22-mediated B-cell receptor regulation 10 2.14E-08 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 FCERI signaling 10 2.14E-08 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Classical antibody-mediated complement activation 10 3.31E-08 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Role of LAT2/NTAL/LAB on calcium mobilization 10 8.38E-08 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 FCGR activation 10 7.38E-08 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Initial triggering of complement 10 1.36E-07 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Role of phospholipids in phagocytosis 10 3.31E-07 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 FCERI-mediated Ca^2+ mobilization 10 5.49E-07 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 FCERI-mediated MAPK activation 10 4.97E-07 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Antigen activates B-cell receptor leading to the generation of second messengers 10 8.82E-07 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Regulation of actin dynamics for phagocytic cup formation 10 6.50E-06 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 CERI-mediated NF-kB activation 10 2.18E-05 IGLV2-11, IGLV2-8, IGLV3-19, IGKV1-5, IGLV1-44, IGLV2-23, IGKV5-2, IGKV4-1, IGLC2, and IGKV3-15 Platelet degranulation 9 1.01E-04 VWF, APP, F5, PPBP, CLU, PF4, SPARC, ITGB3, and ITGA2B Platelet adhesion to exposed collagen 4 5.69E-04 VWF, GP6, GP1BA, and GP9 GP1b-IX-V activation signaling 3 0.005 VWF, GP1BA, and GP9 Mitotic prometaphase 6 0.007 SPC24, KIF2C, CDC20, AURKB, TUBB1, and TUBA1A ECM proteoglycans 5 0.01 APP, ITGB5, SPARC, ITGB3, and ITGA2B GRB2:SOS provides linkage to MAPK signaling for Integrins 3 0.012 SPC24, KIF2C, CDC20, AURKB, TUBB1, and TUBA1A p130Cas linkage to MAPK signaling for integrins 3 0.012 VWF, ITGB3, and ITGA2B Resolution of Sister Chromatid Cohesion 6 0.012 VWF, ITGB3, and ITGA2B Integrin cell surface interactions 5 0.016 ICAM1, VWF, ITGB5, ITGB3, and ITGA2B RHO GTPases Activate Formins 6 0.018 SPC24, KIF2C, CDC20, AURKB, UBE2C, TUBB1, and TUBA1A Separation of Sister Chromatids 7 0.018 SPC24, KIF2C, CDC20, AURKB, TUBB1, and TUBA1A Cell surface interactions at the vascular wall 4 0.023 GP6, ESAM, PF4, and TREM1 Intrinsic pathway of fibrin clot formation 3 0.025 PRKAR2B, TUBB1, TUBA1A, and NTU Hedgehog 'off' state 4 0.025 VWF, GP1BA, and GP9 Integrin alpha IIb beta 3 signaling 3 0.027 VWF, ITGB3, and ITGA2B Syndecan interactions 3 0.037 SDC1, ITGB5, and ITGB3 [101]Open in a new tab DEGs with a significant change between children with AD and healthy control children (cutoff FC ≥1.5 and FDR <0.05) were used for GO enrichment and pathway analyses using DAVID database. KEGG and Reactome pathway analyses were used to determine the pathways of DEGs between two groups. Abbreviations: AD, atopic dermatitis; Akt, protein kinase B; Ca^2+, calcium ion; DEG, differentially expressed gene; ECM, extracellular matrix; FC, fold change; FCERI, Fc-epsilon receptor; FDR, false discovery rate; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; MMP, matrix metalloproteinase; PI3K, phosphoinositide 3-kinase. Construction of protein‒protein interaction network and module analysis To explore interactions among the DEG genes, STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) analysis was applied, and the most important modules were then screened and visualized using Cytoscape software. A protein‒protein interaction (PPI) network containing 82 connected nodes (proteins) and 194 interaction edges (interactions of proteins), where the average degree of connectivity (i.e., the average number of neighbors) was 4.732, is presented in [102]Figure 5a. The hub nodes with the greatest number of neighbors (≥8), such as TNF, IL-1β, Von Willebrand factor, and ITGB3, were identified (labeled in red in [103]Figure 5a) and analyzed by GO enrichment and pathway analyses ([104]Table 6). The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the hub genes were involved in the cytokine‒cytokine receptor interaction, hematopoietic cell lineage, extracellular matrix‒receptor interaction, platelet activation, cell division, and other pathways. In addition, two significant modules with 10 nodes were obtained from the PPI network of DEGs using Molecular Complex Detection ([105]Figure 5b and c). Enrichment analysis suggested that the genes in the first significant module ([106]Figure 5b) were mainly associated with functional terms in the category BP, including cell division, cell proliferation, and mitotic nuclear division. In the category CC, the genes in this module were significantly enriched in cytosol and nucleus, and in the category MF, the genes were mainly enriched in protein and adenosine triphosphate binding. The genes in the second module ([107]Figure 5c) were significantly enriched in inflammatory response, chemokine-mediated signaling, platelet degranulation and activation, immune response, and signal transduction in the category BP. In the category CC, the genes were significantly enriched in the extracellular region, extracellular space, and platelet alpha granule lumen, and in the category MF, the genes were mainly enriched in chemokine activity and CXCR chemokine receptor binding. Furthermore, results from the Kyoto Encyclopedia of Genes and Genomes analysis showed that the genes in this significant module were associated with chemokine signaling pathway and cytokine‒cytokine receptor interaction ([108]Table 7). Figure 5. [109]Figure 5 [110]Open in a new tab PPI networks. (a) PPI network with 82 nodes. In the network, nodes represent proteins, and lines (edges) represent the interactions between proteins. Red nodes represent the hub nodes with a large number of neighbors (≥8). (b) A first significant module with 12 nodes identified by MCODE. (c) A second significant module with 12 nodes identified by MCODE. MCODE, Molecular Complex Detection; PPI, protein‒protein interaction. Table 6. GO Enrichment and Pathway Analyses of Hub Genes GO Term Gene Count P-Value Biological process Platelet degranulation 7 5.39E-10 Platelet activation 5 4.64E-06 Extracellular matrix organization 5 3.80E-05 Cell division 5 3.56E-04 Negative regulation of extrinsic apoptotic signaling pathway in absence of ligand 3 6.29E-04 Platelet aggregation 3 7.73E-04 Blood coagulation 4 7.86E-04 Cell adhesion 5 9.88E-04 Mitotic nuclear division 4 0.002 Anaphase-promoting complex-dependent catabolic process 3 0.003 Positive regulation of calcidiol 1-monooxygenase activity 2 0.003 Sequestering of triglyceride 2 0.004 Sister chromatid cohesion 3 0.005 Positive regulation of fever generation 2 0.005 Inflammatory response 4 0.006 Regulation of establishment of endothelial barrier 2 0.007 Positive regulation of protein phosphorylation 3 0.007 Cytokine-mediated signaling pathway 3 0.008 Regulation of chromosome segregation 2 0.008 Negative regulation of lipid storage 2 0.008 Immune response 4 0.008 Positive regulation of ubiquitin-protein ligase activity 2 0.009 Positive regulation of chemokine biosynthetic process 2 0.010 Protein ubiquitination involved in ubiquitin-dependent protein catabolic process 3 0.010 Positive regulation of heterotypic cell-cell adhesion 2 0.011 Regulation of cell proliferation 3 0.015 Regulation of I-kB kinase/NF-kB signaling 2 0.015 Positive regulation of membrane protein ectodomain proteolysis 2 0.015 Positive regulation of VEGF receptor signaling pathway 2 0.016 Negative regulation of lipid catabolic process 2 0.016 Cell‒substrate adhesion 2 0.017 Proteasome-mediated ubiquitin-dependent protein catabolic process 3 0.018 Blood coagulation, intrinsic pathway 2 0.018 Positive regulation of leukocyte chemotaxis 2 0.018 Positive regulation of protein export from the nucleus 2 0.019 Positive regulation of NF-kB import into the nucleus 2 0.021 Regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle 2 0.023 Positive regulation of IL-8 production 2 0.026 Positive regulation of gene expression 3 0.028 Positive regulation of phagocytosis 2 0.029 Lipopolysaccharide-mediated signaling pathway 2 0.032 Protein kinase B signaling 2 0.033 Positive regulation of nitric oxide biosynthetic process 2 0.043 Positive regulation of IL-6 production 2 0.045 Positive regulation of IFN-γ production 2 0.046 Positive regulation of cell division 2 0.047 Cellular component Platelet alpha granule lumen 5 1.72E-07 Cell surface 5 0.001 Extracellular region 7 0.002 Kinetochore 3 0.003 Extracellular space 6 0.006 Membrane 7 0.012 Platelet alpha granule membrane 2 0.012 Spindle mid-zone 2 0.018 Anaphase-promoting complex 2 0.021 Cytosol 8 0.023 ER to Golgi transport vesicle 2 0.024 Integrin complex 2 0.025 Integral component of plasma membrane 5 0.038 Spindle microtubule 2 0.040 Cytoplasmic microtubule 2 0.047 Molecular function Protein binding 16 0.002 Protease binding 3 0.005 Identical protein binding 5 0.006 Extracellular matrix binding 2 0.026 Enzyme binding 3 0.043 Chemokine activity 2 0.048 KEGG pathway Hematopoietic cell lineage 5 1.09E-05 ECM‒receptor interaction 4 3.96E-04 Platelet activation 4 0.001 Cytokine‒cytokine receptor interaction 4 0.008 Hypertrophic cardiomyopathy 3 0.008 Dilated cardiomyopathy 3 0.009 Osteoclast differentiation 3 0.021 Alzheimer's disease 3 0.033 Focal adhesion 3 0.048 [111]Open in a new tab Hub genes identified in PPI network were used for GO enrichment and pathway analyses using DAVID database. Abbreviations: ECM, extracellular matrix; ER, endoplasmic reticulum; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein‒protein interaction. Table 7. GO Enrichment and Pathway Analyses of Significant Modules GO Term Gene Count P-Value Module 1 Biological process Cell division 6 4.50E-07 Mitotic nuclear division 5 5.52E-06 Sister chromatid cohesion 4 1.83E-05 Anaphase-promoting complex-dependent catabolic process 3 7.70E-04 Cell proliferation 4 7.82E-04 Protein ubiquitination involved in ubiquitin-dependent protein Catabolic process 3 0.003 Regulation of chromosome segregation 2 0.004 Positive regulation of ubiquitin-protein ligase activity 2 0.005 Proteasome-mediated ubiquitin-dependent protein catabolic process 3 0.005 Regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle 2 0.012 Negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle 2 0.037 Positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition 2 0.040 Cellular component Kinetochore 3 6.88E-04 Cytosol 7 0.002 Anaphase-promoting complex 2 0.011 Spindle microtubule 2 0.022 Nucleus 7 0.024 Cytoplasmic microtubule 2 0.025 Nucleoplasm 5 0.036 Condensed chromosome kinetochore 2 0.042 Molecular Function Protein binding 10 0.003 ATP binding 4 0.039 KEGG pathway Ubiquitin mediated proteolysis 2 0.039 Module 2 Biological process Platelet degranulation 7 3.80E-12 Positive regulation of leukocyte chemotaxis 3 3.89E-05 Response to lipopolysaccharide 4 7.36E-05 Chemokine-mediated signaling pathway 3 6.23E-04 Inflammatory response 4 8.66E-04 Platelet activation 3 0.002 Regulation of cell proliferation 3 0.004 Extracellular matrix organization 3 0.005 Response to lead ion 2 0.007 G-protein coupled receptor signaling pathway 4 0.010 Immune response 3 0.020 Signal transduction 4 0.020 Innate immune response 3 0.021 Response to peptide hormone 2 0.023 Positive regulation of TNF production 2 0.025 Negative regulation of angiogenesis 2 0.033 Cellular component Platelet alpha granule lumen 7 4.75E-14 Extracellular region 9 3.03E-08 Extracellular space 8 3.74E-07 cell surface 4 0.002 platelet alpha granule 2 0.007 ER to Golgi transport vesicle 2 0.013 mitochondrial membrane 2 0.045 Molecular function chemokine activity 3 2.93E-04 CXCR chemokine receptor binding 2 0.005 collagen binding 2 0.032 chaperone binding 2 0.042 KEGG pathway Chemokine signaling pathway 4 3.66E-04 Cytokine‒cytokine receptor interaction 3 0.017 [112]Open in a new tab Two significant modules identified in PPI network were used for GO enrichment and pathway analyses using DAVID database. Abbreviations: ATP, adenosine triphosphate; ER, endoplasmic reticulum; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein‒protein interaction. Discussion AD is a complex disease associated with immunological and epidermal barrier dysfunctions. Most of our knowledge in the field of AD is based on studies performed in adult patients with AD, although remarkable differences between pediatric and adult AD have been shown recently. Therefore, it is of great importance to identify the molecular basis of pediatric AD and elucidate the biomarkers that could help to identify young patients at risk at an earlier stage of life and to explore new therapies in pediatric AD. Given that more than half of all cases of AD begin during the first year of life, we aimed to discover signature biomarkers of AD in infants. Considering that skin biopsies are very difficult to obtain at such a young age, that AD generates a systemic immunological response, and that blood is a noninvasive source of biological tissue, we analyzed blood profiles of pediatric patients with AD in the first year of life. Using RNA-seq transcriptome profile of peripheral blood cells obtained from infants with AD or healthy infants, we identified 178 genes differentially expressed in pediatric patients with AD: 115 were upregulated, and 63 were downregulated. To further investigate the functions of the DEGs, GO functional annotation and pathway enrichment analysis were used on the basis of the DAVID database. The GO analysis showed that DEGs were associated with immune responses, inflammatory responses, regulation of immune responses, and platelet activation, which are all known to be AD related. The results of the pathway analysis indicated that the DEGs were enriched in immunoregulatory interactions between a lymphoid and a nonlymphoid cell, hematopoietic cell lineage, phosphoinositide 3-kinase‒protein kinase B signaling pathway, cytokine‒cytokine receptor interaction, NK cell‒mediated cytotoxicity, and platelet activation. Randomly selected DEGs were further validated in a larger number of samples collected from patients with AD in the first year of life using RT-qPCR. Among highly upregulated genes, we identified IL1β, previously shown to be upregulated in the serum of adult AD ([113]Thijs et al., 2018) and stratum corneum of our pediatric AD collection as reported previously ([114]McAleer et al., 2019). It has been shown to be involved in AD development ([115]Bernard et al., 2017). IL-1β is a potent proinflammatory cytokine that can mediate inflammatory responses by supporting T-cell survival, upregulation of the IL-2 receptor on lymphocytes, enhancing antibody production of B cells, and promoting B-cell proliferation and T helper 17 cell differentiation ([116]Lamkanfi et al., 2011). IL-1β activity is regulated at multiple levels, one of which is controlled by inflammasomes ([117]Schroder and Tschopp, 2010). Recent findings suggest that inflammasome-dependent IL-1β activation plays a role in a variety of disorders, including AD. Of note, among upregulated DEGs, we identified NLRP3, one of the important inflammasome proteins. Another interesting upregulated DEG in our pediatric patients was TREM1. Recently, it has been reported to be highly expressed in lesional skin and serum of adult AD ([118]Suarez-Farinas et al., 2015). It has also been reported to be expressed in psoriasis and has been suggested to be a therapeutic target to modify the effects of inflammatory myeloid dendritic cells in psoriasis ([119]Hyder et al., 2013). TREM1 (CD354) is a cell surface receptor that is expressed on various types of cells: monocytes, neutrophils NK cells, dendritic cells, and B and [120]T cells and has been implicated in innate and adaptive immune responses. Activation of TREM1 was shown to result in the production of a variety of inflammatory cytokines, including TNF, IL6, MCP1, and IL-1β, and amplification of toll-like receptor‒initiated inflammation ([121]Roe et al., 2014). Of interest, TNF was highly expressed in the blood cells of our pediatric AD collection. It has been shown to be involved in inflammatory processes in AD ([122]Jacobi et al., 2005; [123]Sumimoto et al., 1992). Furthermore, TNF together with the T helper 2 cytokines induced AD-like features in a skin model ([124]Danso et al., 2014). In addition, TNF together with TNF-like weak inducer of apoptosis induced keratinocyte apoptosis in AD skin ([125]Zimmermann et al., 2011). Another interesting group of genes found to be upregulated in the blood of pediatric patients with AD included early growth response genes (EGR1, EGR2, and EGR3), a family of zinc-finger transcription factors. EGR1, an important player in the regulation of cell growth, differentiation, cell survival, and immune responses, has been reported to be upregulated in psoriatic skin lesions ([126]Jeong et al., 2014). EGR2/3 is known to play a crucial role in the regulation of the immune system. They control inflammation, regulate B- and T-cell function in adaptive immune responses, and have been suggested to be involved in preventing the development of autoimmune disease ([127]Morita et al., 2016) and limiting immunopathology during productive adaptive immune responses ([128]Li et al., 2012). Notably, EGR2 is located in a susceptibility locus for AD identified by GWAS in the Japanese population ([129]Hirota et al., 2012). Among the downregulated genes, we identified IL18R1 and IL18RAP, also previously found to be associated with AD ([130]Hirota et al., 2012). IL18RAP enhances the IL18-binding activity of the IL18 receptor (IL18R1) and plays a role in signaling by IL-18, a pleiotropic immune regulator. IL-18 plays a strong proinflammatory role by inducing IFN-γ. Previous studies have implicated IL-18 in the pathogenesis of AD. It has been shown to contribute to the spontaneous development of AD-like skin lesions in a transgenic mouse model ([131]Konishi et al., 2002). It has been reported to be elevated in skin lesions of adults with AD. In our previous study, we analyzed plasma and stratum corneum biomarkers in this collection of patients and showed that IL-18 was observed in very high levels in the stratum corneum of pediatric patients; however, no difference was observed in IL-18 plasma levels ([132]McAleer et al., 2019). Another study showed that PBMCs from patients with AD have a decreased IL-18 expression and capacity to produce IFN-γ, which is inversely correlated with serum IgE concentrations ([133]Higashi et al., 2001), suggesting an IL-18 role in the skewing of the immune system in patients with AD. Another gene significantly downregulated in AD infants was GLDC. GLDC, glycine metabolism and the metabolic enzyme glycine decarboxylase, is a key enzyme of the mitochondrial glycine cleavage system ([134]Hiraga and Kikuchi, 1980). GLDC plays important role in many human cancers ([135]Zhang et al., 2012). It has been shown to be differentially expressed in psoriatic skin ([136]Rittie et al., 2016). Interestingly, GLDC has been reported to be differentially expressed in AD-like‒reconstructed human epidermis ([137]Evrard et al., 2021), suggesting its involvement in AD development. A PPI network among the screened DEGs was predicted. The PPI analysis allowed us to determine significant modules and hub genes. In the resulting PPI network, 18 hub genes with the highest degree of connectivity were selected, which included IL1β, Von Willebrand factor gene VWF, PF4, ITGB3, ITGA2B, APP, F5, AURKB, SKA3, MELK, CDC20, PPBP, NCAPG, GTSE1, KIF2C, GP1BA, UBE2C, and TNF. Pathway analysis revealed that the hub genes were involved in the cytokine‒cytokine receptor interaction, hematopoietic cell lineage, extracellular matrix‒receptor interaction, cell division, platelet activation, and other pathways. In addition, two significant modules were identified. The genes in the first significant module were mainly associated with cell division, cell proliferation, and mitotic nuclear division. The genes in the second module were significantly enriched in inflammatory response, chemokine-mediated signaling, platelet degranulation and activation, immune response, and signal transduction and were associated with chemokine signaling pathway and cytokine‒cytokine receptor interaction. We wondered whether the hub genes could be linked to AD or other skin inflammatory diseases. The important role of IL-1β and TNF in AD has been shown earlier in this report. Von Willebrand factor, a key player in hemostasis, has been reported in relation to cutaneous inflammation ([138]Hillgruber et al., 2014). Increased expression of PF4 has been proposed to play an important role in the etiology of AD ([139]Watanabe et al., 1999). Increased ITGB3 expression has been reported in T helper 17‒associated skin inflammatory diseases such as psoriasis ([140]Goedkoop et al., 2004) and psoriatic arthritis ([141]Canete et al., 2004). A significant increase in platelet-leukocyte aggregates expressing ITGA2B was found in the blood of mice with chronic hapten-induced allergic dermatitis ([142]Tamagawa-Mineoka et al., 2007). PPBP has been found to be important for regulating excessive inflammation in psoriasis ([143]Oka et al., 2017). Elevated AURKB expression in lesional psoriatic tissues has been suggested to contribute to the development of psoriasis ([144]Liu et al., 2011). Actively proliferating UBE2C+TOP2A+ type 2/type 22 T cells were expanded in lesional AD skin and were either absent or less abundant in nonlesional and healthy samples ([145]He et al., 2020). These findings suggest that identified hub genes could be considered important candidates for prognostic and therapeutic targets of pediatric AD. Taken together, this study showed that blood gene expression profile identified distinct key genes and pathways of early-onset pediatric AD. Observed dramatic changes in the PBMC transcriptome were predominantly related to immune responses in AD. New data assessed from this study may help to better understand the processes leading to AD in infants and may serve in the development of novel treatment possibilities. However, to decipher the full mechanism involved in pediatric AD pathogenesis, skin RNA profile should be further investigated in infants with AD. Blood profile along with skin profile in infants with AD could provide us with a larger number of potential biomarkers that may contribute to AD prediction, risk of comorbidity development, and responses to AD treatment in infants. Materials and Methods Patients We recruited infants aged <12 months with moderate-to-severe AD who were treatment naive (apart from the use of emollients and 1% hydrocortisone cream or ointment) along with age-matched healthy controls. The study was approved by the Research Ethics Committee of Children's Health Ireland at Crumlin (Dublin, Ireland) and was conducted in compliance with the Helsinki Declaration. Written informed consent was given by parents or legal guardians for all study subjects. The age of onset of AD was recorded. Severity was assessed by the SCORing Atopic Dermatitis index. Clinical and demographic features are summarized in [146]Table 8. Analysis of cytokine and microRNA biomarkers in this collection has previously been reported ([147]McAleer et al., 2019; [148]Nousbeck et al., 2021). Table 8. Clinical and Demographical Characteristics of the Study Participants Characteristics Patients with AD Healthy Controls Total 27 17 Sex Male 18 11 Female 9 6 Age (mo) Average 6.9 7.94 Range 3-10 3-12 Age of AD onset (wk) Average 9 — Range 4‒20 — SCORAD Average 49.4 — Range 23.4‒91.3 — [149]Open in a new tab Abbreviations: AD, atopic dermatitis; SCORAD, SCORing Atopic Dermatitis. PBMC preparation and RNA isolation PBMCs were isolated from whole blood as previously described ([150]Nousbeck et al., 2021) using histopaque double-gradient density centrifugation (Sigma-Aldrich, St. Louis, MO) and cryopreserved for further analysis. Total RNA was isolated from PBMCs according to RNeasy Mini Kit protocol (Qiagen, Hilden, Germany). RNA concentrations, RNA integrity, and quality of RNA were evaluated using Qubit fluorometer (Thermo Fisher Scientific, Waltham, MA) and RNA 6000 Nano Lab Chips on an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA). RNA samples with optimal RNA integrity number values (≥8) were considered to construct libraries for sequencing. RNA-seq, data processing, and differential expression analysis Library preparation (using Illumina TruSeq stranded mRNAseq library kit) and sequencing were conducted by Edinburgh Genomics, The University of Edinburgh (Edinburgh, United Kingdom). The sequencing of the libraries was performed with Illumina NovaSeq 6000 (100 cycles, 50 base pair paired-end sequencing). Sequencing reads showed excellent quality, with the overall Q30 above 94%. After sequencing, reads were trimmed using Cutadapt ([151]Martin, 2011), and clean paired-end reads were mapped to the human reference genome GRCh38 using STAR software ([152]Dobin et al., 2013). The number of reads for each gene was counted using featureCounts ([153]Liao et al., 2014), and the count matrix was used for differential expression analysis. Differential expression was performed using package DESeq2 in R software (version 3.5.2), considering an expression >20 read counts in at least 25% of the samples, a cutoff of at least 1.5-fold change in expression, and a Benjamini‒Hochberg‒corrected false discovery rate < 0.05. Real-time RT-qPCR The DEGs were further verified using RT-qPCR. Briefly, total RNA was reverse transcribed using SensiFAST cDNA synthesis kit (Bioline, London, United Kingdom). cDNA PCR amplification was carried out using the SensiFAST SYBR Hi-ROX Kit (Bioline) on 7900HT Fast Real-Time PCR System with gene-specific intron-crossing oligonucleotide pairs. Primers are available in [154]Table 9. Results were normalized to GAPDH mRNA levels. Triplicates of each reaction were performed as the mean ± SD. Relative quantification of target mRNA expression was performed using the 2-ΔΔCT method ([155]Livak and Schmittgen, 2001). The normalized expression data were log[2] transformed before data analysis. Table 9. Primers Sequences for RT-qPCR Gene Forward Primer Reverse Primer IL18RAP CCAGGGGTGAATAATTCTGGGT CATTTGTCTGGGGCTTAACTTCT IL1B TTCGACACATGGGATAACGAGG TTTTGCTGTGAGTCCCGGAG TNF CCTCTCTCTAATCAGCCCTCTG GAGGACCTGGGAGTAGATGAG TREM1 GAACTCCGAGCTGCAACTAAA TCTAGCGTGTAGTCACATTTCAC EGR3 CCAACGACATGGGCTCCATT GGTCTCCAGAGGGGTAATAGG GAPDH GAGTCAACGGATTTGGTCGT GACAAGCTTCCCGTTCTCAGCC [156]Open in a new tab GO enrichment and pathway analysis DEGs were submitted to Visualisation and Integrated Discovery analysis (DAVID, version 6.8) ([157]Huang da et al., 2009) for GO term enrichment and pathway analysis using default parameters. Kyoto Encyclopedia of Genes and Genomes and Reactome pathway analyses were used to determine the pathways of DEGs between two groups. Any GO terms and pathways with P < 0.05 were considered significantly enriched. Construction of PPI network and module analysis Associations between DEGs were investigated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) ([158]Szklarczyk et al., 2017) (STRING10.5, [159]http://string-db.org/), and a confidence score >0.6 was considered to indicate significance. Cytoscape software (version 3.6.1) was then used to visualize the PPI network ([160]Shannon et al., 2003). In the network, nodes represented proteins, and lines (edges) represented the interactions. In addition, the most significant modules were identified with the plug-in Molecular Complex Detection (version 1.5.1) with the following settings: degree cutoff of 2, node score cutoff of 0.2, k-core of 2, and a maximum depth of 100, and they were identified by the following criteria: Molecular Complex Detection score >5 and number of nodes >5. Finally, the hub genes in the PPI network were determined, defined as those with a degree of connectivity ≥8. Data availability statement Datasets related to this article can be found at [161]https://osf.io/hfwyt/?viewonly=ececc20afd5d42e2806b11483edb9d0d, hosted at The Open Science Framework. ORCIDs Janna Nousbeck: [162]http://orcid.org/0000-0001-6918-8855 Alan D. Irvine: [163]http://orcid.org/0000-0002-9048-2044 Maeve A. McAleer: [164]http://orcid.org/0000-0001-9958-6504 Conflict of Interest ADI is a consultant/speaker for Sanofi, Regeneron, Lilly, AbbVie, Pfizer, Benevolent AI, Almirall, LEO, and Arena. The remaining authors state no conflict of interest. Acknowledgments