Genetic Variant Near IRS1 is Associated with Type 2 Diabetes, Insulin Resistance and Hyperinsulinemia

Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.

Citing Articles

Identification of Interactive Genetic Loci Linked to Insulin Resistance in Metabolic Syndrome-An Update.

Elfaki I, Mir R, Elnageeb M, Hamadi A, Alharbi Z, Bedaiwi R Medicina (Kaunas). 2025; 61(1).

PMID: 39859066 PMC: 11767019. DOI: 10.3390/medicina61010083.

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

DeForest N, Wang Y, Zhu Z, Dron J, Koesterer R, Natarajan P Nat Commun. 2024; 15(1):8068.

PMID: 39277575 PMC: 11401929. DOI: 10.1038/s41467-024-52105-y.

Multipartite network analysis to identify environmental and genetic associations of metabolic syndrome in the Korean population.

Shin J, Shin N, Park T, Park M Sci Rep. 2024; 14(1):20283.

PMID: 39217223 PMC: 11366034. DOI: 10.1038/s41598-024-71217-5.

Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

Gilliland T, Dron J, Selvaraj M, Trinder M, Paruchuri K, Urbut S Circ Res. 2024; 135(2):265-276.

PMID: 38828614 PMC: 11223949. DOI: 10.1161/CIRCRESAHA.123.323973.

Genetic and inflammatory factors underlying gestational diabetes mellitus: a review.

Ray G, Zeng Q, Kusi P, Zhang H, Shao T, Yang T Front Endocrinol (Lausanne). 2024; 15:1399694.

PMID: 38694942 PMC: 11061502. DOI: 10.3389/fendo.2024.1399694.

References

Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H . Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet. 2008; 40(9):1092-7. DOI: 10.1038/ng.207. View

Jorgensen T, Borch-Johnsen K, Thomsen T, Ibsen H, Glumer C, Pisinger C . A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur J Cardiovasc Prev Rehabil. 2003; 10(5):377-86. DOI: 10.1097/01.hjr.0000096541.30533.82. View

Hojlund K, Staehr P, Hansen B, Green K, Grahame Hardie D, Richter E . Increased phosphorylation of skeletal muscle glycogen synthase at NH2-terminal sites during physiological hyperinsulinemia in type 2 diabetes. Diabetes. 2003; 52(6):1393-402. DOI: 10.2337/diabetes.52.6.1393. View

Lauritzen T, Griffin S, Borch-Johnsen K, Wareham N, Wolffenbuttel B, Rutten G . The ADDITION study: proposed trial of the cost-effectiveness of an intensive multifactorial intervention on morbidity and mortality among people with Type 2 diabetes detected by screening. Int J Obes Relat Metab Disord. 2000; 24 Suppl 3:S6-11. DOI: 10.1038/sj.ijo.0801420. View

Samani N, Erdmann J, Hall A, Hengstenberg C, Mangino M, Mayer B . Genomewide association analysis of coronary artery disease. N Engl J Med. 2007; 357(5):443-53. PMC: 2719290. DOI: 10.1056/NEJMoa072366. View

Barrett J, Hansoul S, Nicolae D, Cho J, Duerr R, Rioux J . Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008; 40(8):955-62. PMC: 2574810. DOI: 10.1038/ng.175. View

Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson J, Thorleifsson G, Manolescu A . Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet. 2007; 39(8):977-83. DOI: 10.1038/ng2062. View

Easton D, Pooley K, Dunning A, Pharoah P, Thompson D, Ballinger D . Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007; 447(7148):1087-93. PMC: 2714974. DOI: 10.1038/nature05887. View

Withers D, Gutierrez J, Towery H, Burks D, Ren J, Previs S . Disruption of IRS-2 causes type 2 diabetes in mice. Nature. 1998; 391(6670):900-4. DOI: 10.1038/36116. View

10.

Saxena R, Voight B, Lyssenko V, Burtt N, de Bakker P, Chen H . Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007; 316(5829):1331-6. DOI: 10.1126/science.1142358. View

11.

Jarvelin M, Elliott P, Kleinschmidt I, Martuzzi M, Grundy C, Hartikainen A . Ecological and individual predictors of birthweight in a northern Finland birth cohort 1986. Paediatr Perinat Epidemiol. 1997; 11(3):298-312. DOI: 10.1111/j.1365-3016.1997.tb00007.x. View

12.

Clausen J, Hansen T, Bjorbaek C, Echwald S, Urhammer S, Rasmussen S . Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet. 1995; 346(8972):397-402. DOI: 10.1016/s0140-6736(95)92779-4. View

13.

Florez J, Sjogren M, Burtt N, Orho-Melander M, Schayer S, Sun M . Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. Diabetes. 2004; 53(12):3313-8. DOI: 10.2337/diabetes.53.12.3313. View

14.

Zeggini E, Parkinson J, Halford S, Owen K, Frayling T, Walker M . Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset. Diabetes. 2004; 53(12):3319-22. DOI: 10.2337/diabetes.53.12.3319. View

15.

Sakamoto H, Yoshimura K, Saeki N, Katai H, Shimoda T, Matsuno Y . Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet. 2008; 40(6):730-40. DOI: 10.1038/ng.152. View

16.

Jellema A, Zeegers M, Feskens E, Dagnelie P, Mensink R . Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia. 2003; 46(7):990-5. DOI: 10.1007/s00125-003-1126-4. View

17.

Poulsen P, Wojtaszewski J, Petersen I, Christensen K, Richter E, Beck-Nielsen H . Impact of genetic versus environmental factors on the control of muscle glycogen synthase activation in twins. Diabetes. 2005; 54(5):1289-96. DOI: 10.2337/diabetes.54.5.1289. View

18.

Stumvoll M, Goldstein B, van Haeften T . Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005; 365(9467):1333-46. DOI: 10.1016/S0140-6736(05)61032-X. View

19.

Florez J, Sjogren M, Agapakis C, Burtt N, Almgren P, Lindblad U . Association testing of common variants in the insulin receptor substrate-1 gene (IRS1) with type 2 diabetes. Diabetologia. 2007; 50(6):1209-17. DOI: 10.1007/s00125-007-0657-5. View

20.

Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G . SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet. 2008; 40(9):1098-102. DOI: 10.1038/ng.208. View