Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Strawbridge, Rona J., Dupuis, Josee, Prokopenko, Iinga, Barker, Adam, Ahlqvist, Emma, 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, Jianan, Makrilakis, Konstantinos, Manning, Alisa K., Martínez-Larrad, Maria Teresa, Narisu, Narisu, Mannila, Maria Nastase, Ohrvik, John, Osmond, Clive, Pascoe, Laura, Payne, Felicity, Sayer, Avan A., Sennblad, Bengt, Silveira, Angela, Stancakova, Alena, Stirrups, Kathy, Swift, Amy J., Syvanen, Ann-Christine, Tuomi, Tiinamaija, van ’t Hooft, Ferdinand M., Walker, Mark, Weedon, Michael N., Xie, Weijia, Zethelius, Bjorn, the DIAGRAM Consortium,, the GIANT Consortium, Coin, Lachlan, the MuTHER Consortium, the CARDIoGRAM Consortium, ., ., ., ., . and . (2011) Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes. Diabetes, 60 10: 2624-2634. doi:10.2337/db11-0415

Author Strawbridge, Rona J.
Dupuis, Josee
Prokopenko, Iinga
Barker, Adam
Ahlqvist, Emma
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, Jianan
Makrilakis, Konstantinos
Manning, Alisa K.
Martínez-Larrad, Maria Teresa
Narisu, Narisu
Mannila, Maria Nastase
Ohrvik, John
Osmond, Clive
Pascoe, Laura
Payne, Felicity
Sayer, Avan A.
Sennblad, Bengt
Silveira, Angela
Stancakova, Alena
Stirrups, Kathy
Swift, Amy J.
Syvanen, Ann-Christine
Tuomi, Tiinamaija
van ’t Hooft, Ferdinand M.
Walker, Mark
Weedon, Michael N.
Xie, Weijia
Zethelius, Bjorn
the DIAGRAM Consortium,
the GIANT Consortium
Coin, Lachlan
the MuTHER Consortium
the CARDIoGRAM Consortium
Title Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
Publication date 2011-01-01
Year available 2011
Sub-type Article (original research)
DOI 10.2337/db11-0415
Open Access Status Not yet assessed
Volume 60
Issue 10
Start page 2624
End page 2634
Total pages 11
Place of publication Alexandria, VA United States
Publisher American Diabetes Association
Language eng
Subject 2724 Internal Medicine
2712 Endocrinology, Diabetes and Metabolism
Abstract 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.
Keyword Endocrinology & Metabolism
Endocrinology & Metabolism
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID RG/08/014/24067
R01 HL087647
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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