Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy.

Autor: DeForest N; Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA., Wang Y; Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA., Zhu Z; Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA., Dron JS; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Programs in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Koesterer R; Programs in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Natarajan P; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Flannick J; Programs in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA., Amariuta T; Halıcıoğlu Data Science Institute, University of California San Diego, La Jolla, CA, USA.; Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA., Majithia AR; Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. amajithia@health.ucsd.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 14; Vol. 15 (1), pp. 8068. Date of Electronic Publication: 2024 Sep 14.
DOI: 10.1038/s41467-024-52105-y
Abstrakt: 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.
(© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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