Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

• Type of Material: Article
• Authors: Arshed Quyyumi, Emory University; Rona J. Strawbridge, Karolinska University Hospital; Josee Dupuis, Boston University School of Public Health; Inga Prokopenko, University of Oxford; Adam Barker, Addenbrooke's Hospital; Emma Ahlqvist, Malmo University Hospital; Denis Rybin, Boston University; John R. Petrie, University of Glasgow; Mary E. Travers, University of Oxford; Nabila Bouatia-Naji, University of Lille; Antigone S. Dimas, Wellcome Trust Centre for Human Genetics; Alexandra Nica, Universite de Geneve Faculte de Medecine; Eleanor Wheeler, Wellcome Trust Sanger Institute; Han Chen, Boston University School of Public Health; Bejamin F. Voight, Broad Institute; Jalal Taneera, Malmo University Hospital; Stavroula Kanoni, Wellcome Trust; John F. Peden, Wellcome Trust Centre for Human Genetics; Fabiola Turrini, Malmo University Hospital; Stefan Gustafsson, Karolinska Institutet; Carina Zabena, Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas; Peter Almgren, Malmo University Hospital; David J.P. Barker, Oregon Health and Science University; Daniel Barnes, Addenbrooke's Hospital; Elaine M. Dennison, Southampton General Hospital; Johan G. Eriksson, National Institute for Health and Welfare; Per Eriksson, Karolinska University Hospital; Elodie Eury, University of Lille; Lasse Folkersen, Karolinska Institutet; Caroline S. Fox, Boston University; Timothy M. Frayling, University of Exeter; Anuj Goel, Wellcome Trust Centre for Human Genetics; Harvest F. Gu, Karolinska Institutet; Momoko Horikoshi, University of Oxford; Bo Isomaa, Folkhalsan; Anne U. Jackson, University of Michigan School of Public Health; Karen A. Jameson, Southampton General Hospital; Eero Kajantie, National Institute for Health and Welfare; Julie Kerr-Conte, University of Lille; Teemu Kuulasmaa, Ita-Suomen yliopisto; Johanna Kuusisto, Ita-Suomen yliopisto; Ruth J.F. Loos, Addenbrooke's Hospital; Jian'an Luan, Addenbrooke's Hospital; Konstantinos Makrilakis, University of Athens Medical School; Alisa K. Manning, Boston University School of Public Health; Maria Teresa Martínez-Larrad, Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas; Narisu Narisu, National Human Genome Research Institute; Maria Nastase Mannila, Karolinska University Hospital; John Öhrvik, Karolinska University Hospital; Clive Osmond, Southampton General Hospital; Laura Pascoe, Newcastle University, United Kingdom; Felicity Payne, Wellcome Trust Sanger Institute; Avan A. Sayer, Southampton General Hospital; Bengt Sennblad, Karolinska University Hospital; Angela Silveira, Karolinska University Hospital; Alena Stančcáková, University of Kuopio; Kathy Stirrups, Wellcome Trust; Amy J. Swift, National Human Genome Research Institute; Ann-Christine Syvänen, Uppsala Universitet; Tiinamaija Tuomi, Folkhälsan Research Centre; Ferdinand M. van 't Hooft, Karolinska University Hospital; Mark Walker, Newcastle University; Michael N. Weedon, University of Exeter; Weijia Xie, University of Exeter; Bjorn Zethelius, Uppsala University; Halit Ongen, Wellcome Trust Centre for Human Genetics; Anders Malarstig, Karolinska University Hospital; Jemma C. Hopewell, University of Oxford; Danish Saleheen, University of Cambridge; John Chambers, Imperial College London; Sarah Parish, University of Oxford; John Danesh, University of Cambridge; Jaspal Kooner, Ealing Hospital NHS Trust; Claes-Goran Ostenson, Karolinska Institutet; Lars Lind, Uppsala University; Cyrus C. Cooper, University of Southampton; Manuel Serrano-Rios, CIBER de Diabetes y Enfermedades Metabólicas Asociadas; Ele Ferrannini, University of Pisa; Tom J. Forsen, University of Helsinki; Robert Clarke, University of Oxford; Maria Grazia Franzosi, Mario Negri Institute for Pharmacological Research; Udo Seedorf, University of Münster; Hugh Watkins, Wellcome Trust Centre for Human Genetics; Philippe Froguel, Université Lille-Nord de France; Paul Johnson, University of Oxford; Panos Deloukas, Wellcome Trust Sanger Institute; Francis S. Collins, National Institutes of Health; Markku Laakso, University of Kuopio; Emmanouli T. Dermitzakis, University of Geneva Medical School; Michael Boehnke, University of Michigan, Ann Arbor; Mark I. McCarthy, University of Oxford; Nicholas J. Wareham, Addenbrooke's Hospital; Leif Groop, Lund University; Francois Pattou, Université Lille-Nord de France; Anna L. Gloyn, University of Oxford; George V. Dedoussis, Harokopio University; Valeriya Lyssenko, Lund University; James B. Meigs, Massachusetts General Hospital; Ines Barroso, Wellcome Trust Sanger Institute; Richard M. Watanabe, University of Southern California; Erik Ingelsson, Karolinska Institutet; Claudia Langenberg, Addenbrooke's Hospital; Anders Hamsten, Karolinska Institutet; Jose C. Flores, Broad Institute
• Language: English
• Date: 2011-10-01
• Publisher: American Diabetes Association
• Publication Version: Final Published Version
• Copyright Statement: © 2011 by the American Diabetes Association.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.2337/db11-0415
• Title of Journal or Parent Work: Diabetes
• ISSN: 0012-1797
• Volume: 60
• Issue: 10
• Start Page: 2624
• End Page: 2634
• Grant/Funding Information: See supplemental materials for funding information.
• Keywords: Female; Genetic Variation; Diabetes Mellitus, Type 2; Humans; Polymorphism, Single Nucleotide; Fasting; Insulin; Male; Genome, Human; Adult; Proinsulin; Genotype
• Research Categories: Biology, Biostatistics; Biology, Cell; Health Sciences, General

Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-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 ;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 × 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, SLC30A8, 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 3 10 -4 ), improved b-cell function (P = 1.1 × 10 -5 ), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 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.