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

Research output: Contribution to journalArticle

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

Details

Authors
  • Rona J. Strawbridge
  • Josee Dupuis
  • Inga Prokopenko
  • Adam Barker
  • 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
  • Francois Pattou
  • Anna L. Gloyn
  • George V. Dedoussis
  • James B. Meigs
  • Ines Barroso
  • Richard M. Watanabe
  • Erik Ingelsson
  • Claudia Langenberg
  • Anders Hamsten
  • Jose C. Florez
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)2624-2634
JournalDiabetes
Volume60
Issue number10
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes