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Author Notes:

Corresponding authors: Jose C. Florez, jcflorez@partners.org; Claudia Langenberg, claudia.langenberg@mrc-epid.cam.ac.uk; and Anders Hamsten, anders.hamsten@ki.se.

R.J.S., J.Du., I.P., A.B., and E.A. contributed equally to this work.

A full list of the DIAGRAM Consortium, the GIANT Consortium, the MuTHER Consortium, the CARDIoGRAM Consortium, and the C4D Consortium investigators is provided in the supplemental materials.


Research Funding:

See supplemental materials for funding information.


  • Adult
  • Diabetes Mellitus, Type 2
  • Fasting
  • Female
  • Genetic Variation
  • Genome, Human
  • Genotype
  • Humans
  • Insulin
  • Male
  • Polymorphism, Single Nucleotide
  • Proinsulin

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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Journal Title:



Volume 60, Number 10


, Pages 2624-2634

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2011 by the American Diabetes Association.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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