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; Claudia Langenberg; Anders Hamsten; Jose C. Florez; 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

PMCID: PMC3178302

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 - without role: Rona J. Strawbridge - Karolinska Institutet
Josee Dupuis - Boston University
Inga Prokopenko - University of Oxford
Adam Barker - Massachusetts Rehabilitation Commission
Emma Ahlqvist - Lund University
Denis Rybin - Boston University
John R. Petrie - University of Glasgow
Mary E. Travers - University of Oxford
Nabila Bouatia-Naji - Univ Lille Nord France, Lille, France
Antigone S. Dimas - University of Oxford
Alexandra Nica - University of Geneva
Eleanor Wheeler - Wellcome Sanger Institute
Han Chen - Boston University
Benjamin F. Voight - Broad Institute
Jalal Taneera - Lund University
Stavroula Kanoni - Harokopio University of Athens
John F. Peden - University of Oxford
Fabiola Turrini - Lund University
Stefan Gustafsson - Karolinska Institutet
Carina Zabena - CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain
Peter Almgren - Lund University
David J. P. Barker - Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97201 USA
Daniel Barnes - Massachusetts Rehabilitation Commission
Elaine M. Dennison - University of Southampton
Johan G. Eriksson - Natl Inst Hlth & Welf, Helsinki, Finland
Per Eriksson - Karolinska Institutet
Elodie Eury - University of Lille
Lasse Folkersen - Karolinska Institutet
Caroline S. Fox - Framingham Heart Study
Timothy M. Frayling - University of Exeter
Anuj Goel - University of Oxford
Harvest F. Gu - Karolinska Institutet
Momoko Horikoshi - University of Oxford
Bo Isomaa - Folkhalsan Res Ctr, Helsinki, Finland
Anne U. Jackson - Biostat
Karen A. Jameson - University of Southampton
Eero Kajantie - Natl Inst Hlth & Welf, Helsinki, Finland
Julie Kerr-Conte - Univ Lille Nord France, Lille, France
Teemu Kuulasmaa - College Station Medical Center
Johanna Kuusisto - College Station Medical Center
Ruth J. F. Loos - Massachusetts Rehabilitation Commission
Jian'an Luan - Massachusetts Rehabilitation Commission
Konstantinos Makrilakis - National and Kapodistrian University of Athens
Alisa K. Manning - Boston University
Maria Teresa Martinez-Larrad - CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid, Spain
Narisu Narisu - Natl Human Genome Res Inst, NIH, Bethesda, MD USA
Maria Nastase Mannila - Karolinska Institutet
John Ohrvik - Karolinska Institutet
Clive Osmond - University of Southampton
Laura Pascoe - Newcastle Univ, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
Felicity Payne - Wellcome Sanger Institute
Avan A. Sayer - University of Southampton
Bengt Sennblad - Karolinska Institutet
Angela Silveira - Karolinska Institutet
Alena Stancakova - College Station Medical Center
Kathy Stirrups
Amy J. Swift - Natl Human Genome Res Inst, NIH, Bethesda, MD USA
Ann-Christine Syvanen - Uppsala University
Tiinamaija Tuomi - Folkhalsan Res Ctr, Helsinki, Finland
Ferdinand M. van 't Hooft - Karolinska Institutet
Mark Walker - University of Newcastle Australia
Michael N. Weedon - University of Exeter
Weijia Xie - University of Exeter
Bjorn Zethelius - Uppsala University
Halit Ongen - University of Oxford
Anders Malarstig - Karolinska Institutet
Jemma C. Hopewell - University of Oxford
Danish Saleheen - University of Cambridge
John Chambers - Ealing Hosp NHS Trust, Middlesex, England
Sarah Parish - University of Oxford
John Danesh - University of Cambridge
Jaspal Kooner - Ealing Hosp NHS Trust, Middlesex, England
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 - Mylan
Udo Seedorf - University of Münster
Hugh Watkins - University of Oxford
Philippe Froguel - University of Lille
Paul Johnson - University of Oxford
Panos Deloukas
Francis S. Collins
Markku Laakso - College Station Medical Center
Emmanouil T. Dermitzakis - University of Geneva
Michael Boehnke - Biostat
Mark I. McCarthy - University of Oxford
Nicholas J. Wareham - Massachusetts Rehabilitation Commission
Leif Groop - Lund University
Francois Pattou - Univ Lille Nord France, Lille, France
Anna L. Gloyn - University of Oxford
George V. Dedoussis - Harokopio University of Athens
Valeriya Lyssenko - Lund University
James B. Meigs - College Station Medical Center
Ines Barroso - Wellcome Sanger Institute
Richard M. Watanabe - Supreme Council Of Health
Erik Ingelsson - Karolinska Institutet
Claudia Langenberg - Massachusetts Rehabilitation Commission
Anders Hamsten - Karolinska Institutet
Jose C. Florez - Broad Institute
C4D Consortium
Publication Details: Diabetes (New York, N.Y.), Vol.60(10), pp.2624-2634
Publisher: Amer Diabetes Assoc
Number of pages: 11
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 R56DK062370 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) ZIAHG000024 / NATIONAL HUMAN GENOME RESEARCH INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI) DK062370; R01 DK078616; K24 DK080140 / NIDDK NIH HHS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
Identifiers: 9936553808331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article