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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

Strawbridge, Rona J.; Dupuis, Josee; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma LU ; Rybin, Denis; Petrie, John R.; Travers, Mary E.; Bouatia-Naji, Nabila and Dimas, Antigone S., et al. (2011) In Diabetes 60(10). p.2624-2634
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.... (More)
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 (Less)
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publication status
published
subject
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Diabetes
volume
60
issue
10
pages
2624 - 2634
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000295998700022
  • scopus:80053405321
ISSN
1939-327X
DOI
10.2337/db11-0415
language
English
LU publication?
yes
id
75097998-11b8-4c18-ac0b-d5222bdf3f42 (old id 2211451)
date added to LUP
2011-12-01 08:26:56
date last changed
2017-11-12 03:39:55
@article{75097998-11b8-4c18-ac0b-d5222bdf3f42,
  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 &lt; 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},
  author       = {Strawbridge, Rona J. and Dupuis, Josee and Prokopenko, Inga and Barker, Adam and Ahlqvist, Emma and Rybin, Denis and Petrie, John R. and Travers, Mary E. and Bouatia-Naji, Nabila and Dimas, Antigone S. and Nica, Alexandra and Wheeler, Eleanor and Chen, Han and Voight, Benjamin F. and Taneera, Jalal and Kanoni, Stavroula and Peden, John F. and Turrini, Fabiola and Gustafsson, Stefan and Zabena, Carina and Almgren, Peter and Barker, David J. P. and Barnes, Daniel and Dennison, Elaine M. and Eriksson, Johan G. and Eriksson, Per and Eury, Elodie and Folkersen, Lasse and Fox, Caroline S. and Frayling, Timothy M. and Goel, Anuj and Gu, Harvest F. and Horikoshi, Momoko and Isomaa, Bo and Jackson, Anne U. and Jameson, Karen A. and Kajantie, Eero and Kerr-Conte, Julie and Kuulasmaa, Teemu and Kuusisto, Johanna and Loos, Ruth J. F. and Luan, Jian'an and Makrilakis, Konstantinos and Manning, Alisa K. and Teresa Martinez-Larrad, Maria and Narisu, Narisu and Mannila, Maria Nastase and Ohrvik, John and Osmond, Clive and Pascoe, Laura and Payne, Felicity and Sayer, Avan A. and Sennblad, Bengt and Silveira, Angela and Stancakova, Alena and Stirrups, Kathy and Swift, Amy J. and Syvanen, Ann-Christine and Tuomi, Tiinamaija and van 't Hooft, Ferdinand M. and Walker, Mark and Weedon, Michael N. and Xie, Weijia and Zethelius, Bjorn and Ongen, Halit and Malarstig, Anders and Hopewell, Jemma C. and Saleheen, Danish and Chambers, John and Parish, Sarah and Danesh, John and Kooner, Jaspal and Ostenson, Claes-Goran and Lind, Lars and Cooper, Cyrus C. and Serrano-Rios, Manuel and Ferrannini, Ele and Forsen, Tom J. and Clarke, Robert and Franzosi, Maria Grazia and Seedorf, Udo and Watkins, Hugh and Froguel, Philippe and Johnson, Paul and Deloukas, Panos and Collins, Francis S. and Laakso, Markku and Dermitzakis, Emmanouil T. and Boehnke, Michael and McCarthy, Mark I. and Wareham, Nicholas J. and Groop, Leif and Pattou, Francois and Gloyn, Anna L. and Dedoussis, George V. and Lyssenko, Valeriya and Meigs, James B. and Barroso, Ines and Watanabe, Richard M. and Ingelsson, Erik and Langenberg, Claudia and Hamsten, Anders and Florez, Jose C.},
  issn         = {1939-327X},
  language     = {eng},
  number       = {10},
  pages        = {2624--2634},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes},
  url          = {http://dx.doi.org/10.2337/db11-0415},
  volume       = {60},
  year         = {2011},
}