Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 Sep 2024
14 Sep 2024
Historique:
received:
22
11
2023
accepted:
27
08
2024
medline:
15
9
2024
pubmed:
15
9
2024
entrez:
14
9
2024
Statut:
epublish
Résumé
Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.
Identifiants
pubmed: 39277575
doi: 10.1038/s41467-024-52105-y
pii: 10.1038/s41467-024-52105-y
doi:
Substances chimiques
Triglycerides
0
Cholesterol, HDL
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8068Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)
ID : R01DK123422
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R01HL159760
Informations de copyright
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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