Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
Authors: Strawbridge Rona J. , Dupuis Josée , Prokopenko Inga , Barker Adam , Ahlqvist Emma , Rybin Denis , Petrie John R. , Travers Mary E. , Bouatia-Naji Nabila , Dimas Antigone S. , Nica Alexandra , Wheeler Eleanor , Chen Han , Voight Benjamin F. , Taneera Jalal , Kanoni Stavroula , Peden John F. , Turrini Fabiola , Gustafsson Stefan , Zabena Carina , Almgren Peter , Barker David J.P. , Barnes Daniel , Dennison Elaine M. , Eriksson Johan G. , Eriksson Per , Eury Elodie , Folkersen Lasse , Fox Caroline S. , Frayling Timothy M. , Goel Anuj , Gu Harvest F. , Horikoshi Momoko , Isomaa Bo , Jackson Anne U. , Jameson Karen A. , Kajantie Eero , Kerr-Conte Julie , Kuulasmaa Teemu , Kuusisto Johanna , Loos Ruth J.F. , Luan Jian'an , Makrilakis Konstantinos , Manning Alisa K. , Martínez-Larrad María Teresa , Narisu Narisu , Nastase Mannila Maria , Öhrvik John , Osmond Clive , Pascoe Laura , Payne Felicity , Sayer Avan A. , Sennblad Bengt , Silveira Angela , Stančáková Alena , Stirrups Kathy , Swift Amy J. , Syvänen Ann-Christine , Tuomi Tiinamaija , van 't Hooft Ferdinand M. , Walker Mark , Weedon Michael N. , Xie Weijia , Zethelius Björn ,   the DIAGRAM Consortium,   the GIANT Consortium,   the MuTHER Consortium,   the CARDIoGRAM Consortium,   the C4D Consortium, Ongen Halit , Mälarstig Anders , Hopewell Jemma C. , Saleheen Danish , Chambers John , Parish Sarah , Danesh John , Kooner Jaspal , Östenson Claes-Göran , Lind Lars , Cooper Cyrus C. , Serrano-Ríos Manuel , Ferrannini Ele , Forsen Tom J. , Clarke Robert , Franzosi Maria Grazia , Seedorf Udo , Watkins Hugh , Froguel Philippe , Johnson Paul , Deloukas Panos , Collins Francis S. , Laakso Markku , Dermitzakis Emmanouil T. , Boehnke Michael , McCarthy Mark I. , Wareham Nicholas J. , Groop Leif , Pattou François , Gloyn Anna L. , Dedoussis George V. , Lyssenko Valeriya , Meigs James B. , Barroso Inês , Watanabe Richard M. , Ingelsson Erik , Langenberg Claudia , Hamsten Anders , Florez Jose C. 
Published: August 2011

OBJECTIVE
Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-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 &lt; 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 × 10−4), improved β-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.