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

Rona J. Strawbridge; Josee Dupuis; Inga Prokopenko; Adam Barker; Emma Ahlqvist; Denis Rybin; John R. Petrie; Mary E. Travers; Nabila Bouatia-Naji; Antigone S. Dimas; Alexandra Nica; Eleanor Wheeler; Han Chen; Benjamin F. Voight; Jalal Taneera; Stavroula Kanoni; John F. Peden; Fabiola Turrini; Stefan Gustafsson; Carina Zabena; Peter Almgren; David J. P. Barker; Daniel Barnes; Elaine M. Dennison; Johan G. Eriksson; Per Eriksson; Elodie Eury; Lasse Folkersen; Caroline S. Fox; Timothy M. Frayling; Anuj Goel; Harvest F. Gu; Momoko Horikoshi; Bo Isomaa; Anne U. Jackson; Karen A. Jameson; Eero Kajantie; Julie Kerr-Conte; Teemu Kuulasmaa; Johanna Kuusisto; Ruth J. F. Loos; Jian'an Luan; Konstantinos Makrilakis; Alisa K. Manning; Maria Teresa Martinez-Larrad; Narisu Narisu; Maria Nastase Mannila; John Ohrvik; Clive Osmond; Laura Pascoe; Felicity Payne; Avan A. Sayer; Bengt Sennblad; Angela Silveira; Alena Stancakova; Kathy Stirrups; Amy J. Swift; Ann-Christine Syvanen; Tiinamaija Tuomi; Ferdinand M. van 't Hooft; Mark Walker; Michael N. Weedon; Weijia Xie; Bjorn Zethelius; Halit Ongen; Anders Malarstig; Jemma C. Hopewell; Danish Saleheen; John Chambers; Sarah Parish; John Danesh; Jaspal Kooner; Claes-Goran Ostenson; Lars Lind; Cyrus C. Cooper; Manuel Serrano-Rios; Ele Ferrannini; Tom J. Forsen; Robert Clarke; Maria Grazia Franzosi; Udo Seedorf; Hugh Watkins; Philippe Froguel; Paul Johnson; Panos Deloukas; Francis S. Collins; Markku Laakso; Emmanouil T. Dermitzakis; Michael Boehnke; Mark I. McCarthy; Nicholas J. Wareham; Leif Groop; Francois Pattou; Anna L. Gloyn; George V. Dedoussis; Valeriya Lyssenko; James B. Meigs; Ines Barroso; Richard M. Watanabe; Erik Ingelsson; C4D Consortium

doi:10.2337/db11-0415

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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

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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

Rona J. Strawbridge, Josee Dupuis, Inga Prokopenko, Adam Barker, Emma Ahlqvist, Denis Rybin, John R. Petrie, Mary E. Travers, Nabila Bouatia-Naji, Antigone S. Dimas, …

Diabetes (New York, N.Y.), Vol.60(10), pp.2624-2634

01/10/2011

DOI: https://doi.org/10.2337/db11-0415

PMID: 21873549

Abstract

Endocrinology & Metabolism

Life Sciences & Biomedicine

Science & Technology

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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Title: Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
Creators: Rona J. Strawbridge - Karolinska Institutet
Josee Dupuis - Boston University
Inga Prokopenko - Oxford Centre for Diabetes, Endocrinology and Metabolism
Adam Barker - MRC Epidemiology Unit
Emma Ahlqvist - Lund University
Denis Rybin - Boston University
John R. Petrie - University of Glasgow
Mary E. Travers - University of Oxford
Nabila Bouatia-Naji - Université de Lille
Antigone S. Dimas - Wellcome Centre for Human Genetics
Alexandra Nica - University of Geneva
Eleanor Wheeler - Wellcome Sanger Institute
Han Chen - Boston University
Benjamin F. Voight - Broad Institute
Jalal Taneera - Malmö University
Stavroula Kanoni - Wellcome Sanger Institute
John F. Peden - Wellcome Centre for Human Genetics
Fabiola Turrini - Malmö University
Stefan Gustafsson - Karolinska Institutet
Carina Zabena - CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain
Peter Almgren - Malmö University
David J. P. Barker - Oregon Health & Science University
Daniel Barnes - Addenbrooke's Hospital
Elaine M. Dennison - Southampton General Hospital
Johan G. Eriksson - Finnish Institute for Health and Welfare
Per Eriksson - Karolinska University Hospital
Elodie Eury - Institut Pasteur de Lille
Lasse Folkersen - Karolinska Institutet
Caroline S. Fox - Brigham and Women's Hospital
Timothy M. Frayling - University of Exeter
Anuj Goel - Wellcome Centre for Human Genetics
Harvest F. Gu - Karolinska Institutet
Momoko Horikoshi - Oxford Centre for Diabetes, Endocrinology and Metabolism
Bo Isomaa - Folkhalsan Res Ctr, Helsinki, Finland
Anne U. Jackson - University of Michigan–Ann Arbor
Karen A. Jameson - MRC Lifecourse Epidemiology Unit
Eero Kajantie - Finnish Institute for Health and Welfare
Julie Kerr-Conte - Université de Lille
Teemu Kuulasmaa - Kuopio University Hospital
Johanna Kuusisto - Kuopio University Hospital
Ruth J. F. Loos - MRC Epidemiology Unit
Jian'an Luan - Massachusetts Rehabilitation Commission
Konstantinos Makrilakis - Laiko General Hospital of Athens
Alisa K. Manning - Boston University
Maria Teresa Martinez-Larrad - CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain
Narisu Narisu - National Human Genome Research Institute
Maria Nastase Mannila - Karolinska Institutet
John Ohrvik - Karolinska Institutet
Clive Osmond - University of Southampton
Laura Pascoe - Newcastle University
Felicity Payne - Wellcome Sanger Institute
Avan A. Sayer - University of Southampton
Bengt Sennblad - Karolinska Institutet
Angela Silveira - Karolinska University Hospital
Alena Stancakova - Kuopio University Hospital
Kathy Stirrups - Wellcome Sanger Institute
Amy J. Swift - National Human Genome Research Institute
Ann-Christine Syvanen - Uppsala University
Tiinamaija Tuomi - Folkhalsan Res Ctr, Helsinki, Finland
Ferdinand M. van 't Hooft - Karolinska Institutet
Mark Walker - Newcastle University
Michael N. Weedon - University of Exeter
Weijia Xie - University of Exeter
Bjorn Zethelius - Uppsala University
Halit Ongen - John Radcliffe Hospital
Anders Malarstig - Karolinska Institutet
Jemma C. Hopewell - University of Oxford
Danish Saleheen - Center for Non-Communicable Diseases
John Chambers - Imperial College London
Sarah Parish - University of Oxford
John Danesh - University of Cambridge
Jaspal Kooner - Imperial College London
Claes-Goran Ostenson - Karolinska Institutet
Lars Lind - Uppsala University
Cyrus C. Cooper - University of Southampton
Manuel Serrano-Rios - CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain
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 - University of Oxford
Philippe Froguel - Imperial College London
Paul Johnson - University of Oxford
Panos Deloukas - Wellcome Sanger Institute
Francis S. Collins - National Institutes of Health
Markku Laakso - Kuopio University Hospital
Emmanouil T. Dermitzakis - University of Geneva
Michael Boehnke - University of Michigan–Ann Arbor
Mark I. McCarthy - Wellcome Centre for Human Genetics
Nicholas J. Wareham - MRC Epidemiology Unit
Leif Groop - Malmö University
Francois Pattou - Université Lille Nord de France
Anna L. Gloyn - University of Oxford
George V. Dedoussis - Harokopio University of Athens
Valeriya Lyssenko - Lund University
James B. Meigs - Massachusetts General Hospital
Ines Barroso - University of Cambridge
Richard M. Watanabe - University of Southern California
Erik Ingelsson - Karolinska Institutet
C4D Consortium
Publication Details: Diabetes (New York, N.Y.), Vol.60(10), pp.2624-2634
Publisher: Amer Diabetes Assoc
Number of pages: 11
Date published: 01/10/2011
Grant note: 090532; 077016/Z/05/Z; 083270/Z/07/Z / Wellcome Trust; European Commission R01HL087647 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) MC_U137686857; MC_UP_A620_1015; MC_UP_A620_1014; MC_U106188470; 81696; MC_PC_U127592696; G0700222; G0801056; G0700222(81696); MC_U127561128; G0601261; G0700931; MC_PC_U127561128; G0601966 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission G0801056B / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission NF-SI-0508-10082 / National Institute for Health Research; National Institute for Health Research (NIHR) ZIACP010201 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) G0700931 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) RG/08/014/24067 / British Heart Foundation ZIAAG007420 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) 08/0003775 / Diabetes UK
Identifiers: 99928851002346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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