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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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The metabolomic profiles of 4262 proficient gene carriers were compared with those of 352 <jats:italic>UGT2B17<\/jats:italic>-deficient, 97 <jats:italic>UGT2B28<\/jats:italic>-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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The unexpectedly broad molecular divergence found in <jats:italic>UGT<\/jats:italic>-deficient metabolomes, which affected\u2009&gt;\u200910% of metabolites, implies their significant influence across various metabolite classes\u2014particularly lipids and amino acids \u2014 extending beyond their known substrates. The metabolic profiles of <jats:italic>UGT2B17<\/jats:italic>-deficient men and <jats:italic>UGT2B28<\/jats:italic>-deficient women were most impacted, with <jats:italic>UGT2B17<\/jats:italic> deficiency affecting various metabolites linked to metabolic diseases, arthritis, and osteoporosis. Metabolites impacted by a <jats:italic>UGT2B28<\/jats:italic> deficiency such as amino acids, were linked to metabolic disorders in women.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13293-025-00708-5","type":"journal-article","created":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T08:33:13Z","timestamp":1745310793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sexual dimorphism in metabolomic and phenotypic spectra of UGT deficiency: findings from the Canadian Longitudinal Study on Aging"],"prefix":"10.1186","volume":"16","author":[{"given":"Ana Lucia","family":"Rivera-Herrera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mich\u00e8le","family":"Rouleau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahukpe Narcisse Ulrich","family":"Singbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Cuppens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Prunier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Droit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Simonyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Guillemette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"issue":"1","key":"708_CR1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s13293-022-00440-4","volume":"13","author":"M Costanzo","year":"2022","unstructured":"Costanzo M, Caterino M, Sotgiu G, Ruoppolo M, Franconi F, Campesi I. 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All participants provided written informed consent upon enrollment into the CLSA.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The opinions expressed in this manuscript are those of the authors and do not reflect the views of the Canadian Longitudinal Study on Aging.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclaimer"}},{"value":"File name: Additional file 1File format. Pdf.Title of data: Supplementary Figures of Sexual Dimorphism in Metabolomic and Phenotypic Spectra of UGT deficiency: Findings from the Canadian Longitudinal Study on Aging.Description of data:","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Additional files"}},{"value":"Metabolites quantified in this study and number of metabolites in each super-pathway that were available for analysis.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig.\u00a01"}},{"value":"Gene expression by sex for (A) UGT2B17 and (B) UGT2B28 in human tissues.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig.\u00a02"}},{"value":"Number of significantly altered metabolites in each UGT KO group relative to the gene-proficient reference group (P\u2009<\u20090.05) by subpathway.","order":9,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig.\u00a03"}},{"value":"Relative abundance of significantly dysregulated metabolites in each KO group.","order":10,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig.\u00a04"}},{"value":"Associations between significantly altered metabolites in UGT2B17 KO and diseases.","order":11,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig.\u00a05"}},{"value":"Associations between significantly altered metabolites in UGT2B17 KO females, UGT2B28 KO males, and diseases.","order":12,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Fig.\u00a06"}},{"value":"File format. Excel.xlsx.Title of data: Supplementary tables of Sexual Dimorphism in Metabolomic and Phenotypic Spectra of UGT deficiency: Findings from the Canadian Longitudinal Study on Aging.Description of data:","order":13,"name":"Ethics","group":{"name":"EthicsHeading","label":"File name: Additional file 2"}},{"value":"Detail of the chronic diseases \/ categories of chronic diseases used in this study.","order":14,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Table 1"}},{"value":"Fold change of the plasma metabolites measured in KO and reference groups.","order":15,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Table 2"}},{"value":"Significant changes in plasma metabolites for postmenopausal women.","order":16,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Table 2.1"}},{"value":"Characteristics of the study groups.","order":17,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Table 3"}},{"value":"Top 5 most changed metabolites in UGT2B17 KO, UGT2B28 KO and Double KO for overall and sex-based analyses.","order":18,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Table 4"}},{"value":"Top 5 most changed metabolites including unknown and partially characterized metabolites in UGT2B17 KO, UGT2B28 KO and Double KO for overall and sex-based analyses.","order":19,"name":"Ethics","group":{"name":"EthicsHeading","label":"Supplementary Table 4.1"}}],"article-number":"26"}}