Abstract

Background

   Two of the most frequently deleted genes in the human genome are the
   UDP-glycosyltransferases UGT2B17 and UGT2B28. They encode metabolic
   enzymes of the glucuronidation pathway that plays a pivotal role in the
   maintenance of cellular homeostasis for a variety of small molecule
   metabolites. These deletions may impact health, yet their effects
   remain poorly understood. We evaluated the impact of UGT deficiency on
   the plasma metabolome and examined the association between altered
   metabolites and health outcomes.

Methods

   The metabolomic profiles of 4262 proficient gene carriers were compared
   with those of 352 UGT2B17-deficient, 97 UGT2B28-deficient, and 20
   double-gene-deficient individuals from the Canadian Longitudinal Study
   on Aging. Significant metabolites found in these comparisons were
   analyzed for their associations with common diseases.

Results

   The unexpectedly broad molecular divergence found in UGT-deficient
   metabolomes, which affected > 10% of metabolites, implies their
   significant influence across various metabolite classes—particularly
   lipids and amino acids — extending beyond their known substrates. The
   metabolic profiles of UGT2B17-deficient men and UGT2B28-deficient women
   were most impacted, with UGT2B17 deficiency affecting various
   metabolites linked to metabolic diseases, arthritis, and osteoporosis.
   Metabolites impacted by a UGT2B28 deficiency such as amino acids, were
   linked to metabolic disorders in women.

Conclusion

   The findings significantly advance our understanding of the metabolic
   landscape associated with these frequently deleted genes in the human
   genome, which may influence susceptibility to various diseases in a
   sex-specific manner, laying the groundwork for determining their
   pathological mechanisms and impact on human health.

Supplementary information

   The online version contains supplementary material available at
   10.1186/s13293-025-00708-5.

   Keywords: CLSA, Metabolomics, Glycosyltransferase, Human gene knockout,
   Metabolic disorders

Highlights

   Divergent metabolomes of deficient glycosyltransferase individuals (UGT
   KO).

   Highest impact of UGT deficiency on lipid profiles.

   Unique metabolic signatures characterize UGT2B17 KO men and UGT2B28 KO
   women.

   UGT KO metabolic signatures are linked to a variety of diseases.

Plain language summary

   The human body constantly produces a variety of small molecules,
   including steroids, bile acids, fatty acids, and hormones.
   UDP-glycosyltransferases (UGTs) are a key family of enzymes that help
   balance these molecules and remove them from the body through a process
   called glucuronidation. Interestingly, two UGT genes, UGT2B17 and
   UGT2B28, are often naturally deleted, meaning some people are born
   without these genes. This gene absence results in a complete deficiency
   of the associated UGT proteins, potentially disrupting the balance of
   certain metabolites in the body. To understand how missing UGT2B17 or
   UGT2B28 affects the body’s full profile of metabolites (known as the
   circulating metabolome), we compared individuals without one or both of
   these genes (deletants) to those with both gene copies (references). We