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Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

Lookup NU author(s): Laura Pascoe, Professor Mark Walker

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Abstract

OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. Diabetes 60:2624-2634, 2011

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Author(s): Strawbridge RJ, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, Petrie JR, Travers ME, Bouatia-Naji N, Dimas AS, Nica A, Wheeler E, Chen H, Voight BF, Taneera J, Kanoni S, Peden JF, Turrini F, Gustafsson S, Zabena C, Almgren P, Barker DJP, Barnes D, Dennison EM, Eriksson JG, Eriksson P, Eury E, Folkersen L, Fox CS, Frayling TM, Goel A, Gu HF, Horikoshi M, Isomaa B, Jackson AU, Jameson KA, Kajantie E, Kerr-Conte J, Kuulasmaa T, Kuusisto J, Loos RJF, Luan JA, Makrilakis K, Manning AK, Martinez-Larrad MT, Narisu N, Mannila MN, Ohrvik J, Osmond C, Pascoe L, Payne F, Sayer AA, Sennblad B, Silveira A, Stancakova A, Stirrups K, Swift AJ, Syvanen AC, Tuomi T, van 't Hooft FM, Walker M, Weedon MN, Xie WJ, Zethelius B, Ongen H, Malarstig A, Hopewell JC, Saleheen D, Chambers J, Parish S, Danesh J, Kooner J, Ostenson CG, Lind L, Cooper CC, Serrano-Rios M, Ferrannini E, Forsen TJ, Clarke R, Franzosi MG, Seedorf U, Watkins H, Froguel P, Johnson P, Deloukas P, Collins FS, Laakso M, Dermitzakis ET, Boehnke M, McCarthy MI, Wareham NJ, Groop L, Pattou F, Gloyn AL, Dedoussis GV, Lyssenko V, Meigs JB, Barroso I, Watanabe RM, Ingelsson E, Langenberg C, Hamsten A, Florez JC, DIAGRAM Consortium, GIANT Consortium, MuTHER Consortium, CARDIoGRAM Consortium, C4D Consortium

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2011

Volume: 60

Issue: 10

Pages: 2624-2634

Print publication date: 26/08/2011

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association

URL: http://dx.doi.org/10.2337/db11-0415

DOI: 10.2337/db11-0415

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