@article{3111423,
    title = "Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes",
    author = "Strawbridge, R.J. and Dupuis, J. and Prokopenko, I. and Barker, A. and Ahlqvist, E. and Rybin, D. and Petrie, J.R. and Travers, M.E. and Bouatia-Naji, N. and Dimas, A.S. and Nica, A.C. and Wheeler, E. and Chen, H. and Voight, B.F. and Taneera, J. and Kanoni, S. and Peden, J.F. and Turrini, F. and Gustafsson, S. and Zabena, C. and Almgren, P. and Barker, D.J.P. and Barnes, D. and Dennison, E.M. and Eriksson, J.G. and Eriksson, P. and Eury, E. and Folkersen, L. and Fox, C.S. and Frayling, T.M. and Goel, A. and Gu, H.F. and Horikoshi, M. and Isomaa, B. and Jackson, A.U. and Jameson, K.A. and Kajantie, E. and Kerr-Conte, J. and Kuulasmaa, T. and Kuusisto, J. and Loos, R.J.F. and Luan, J. and Makrilakis, K. and Manning, A.K. and Martínez-Larrad, M.T. and Narisu, N. and Mannila, M.N. and Öhrvik, J. and Osmond, C. and Pascoe, L. and Payne, F. and Sayer, A.A. and Sennblad, B. and Silveira, A. and Stančcáková, A. and Stirrups, K. and Swift, A.J. and Syvänen, A.-C. and Tuomi, T. and Van't Hooft, F.M. and Walker, M. and Weedon, M.N. and Xie, W. and Zethelius, B. and Scott, L.J. and Steinthorsdottir, V. and Morris, A.P. and Dina, C. and Welch, R.P. and Zeggini, E. and Huth, C. and Aulchenko, Y.S. and Thorleifsson, G. and Mcculloch, L.J. and Ferreira, T. and Grallert, H. and Amin, N. and Wu, G. and Willer, C.J. and Raychaudhuri, S. and McCarroll, S.A. and Hofmann, O.M. and Qi, L. and Segre, A.V. and Van Hoek, M. and Navarro, P. and Ardlie, K. and Balkau, B. and Benediktsson, R. and Bennett, A.J. and Blagieva, R. and Boerwinkle, E. and Bonnycastle, L.L. and Bostrom, K.B. and Bravenboer, B. and Bumpstead, S. and Burtt, N.P. and Charpentier, G. and Chines, P.S. and Cornelis, M. and Couper, D.J. and Crawford, G. and Doney, A.S.F. and Elliott, K.S. and Elliott, A.L. and Erdos, M.R. and Franklin, C.S. and Ganser, M. and Gieger, C. and Grarup, N. and Green, T. and Griffin, S. and Groves, C.J. and Guiducci, C. and Hadjadj, S. and Hassanali, N. and Herder, C. and Johnson, P.R.V. and Jorgensen, T. and Kao, W.H.L. and Klopp, N. and Kong, A. and Kraft, P. and Lauritzen, T. and Li, M. and Lieverse, A. and Lindgren, C.M. and Lyssenko, V. and Marre, M. and Meitinger, T. and Midthjell, K. and Morken, M.A. and Nilsson, P. and Owen, K.R. and Perry, J.R.B. and Petersen, A.-K. and Platou, C. and Proenca, C. and Rathmann, W. and Rayner, N.W. and Robertson, N.R. and Rocheleau, G. and Roden, M. and Sampson, M.J. and Saxena, R. and Shields, B.M. and Shrader, P. and Sigurdsson, G. and Sparso, T. and Strassburger, K. and Stringham, H.M. and Sun, Q. and Thorand, B. and Tichet, J. and Van Dam, R.M. and Van Haeften, T.W. and Van Herpt, T. and Van Vliet-Ostaptchouk, J.V. and Walters, G.B. and Wijmenga, C. and Witteman, J.C.M. and Bergman, R.N. and Cauchi, S. and Collins, F.S. and Gloyn, A.L. and Gyllensten, U. and Hansen, T. and Hide, W.A. and Hitman, G.A. and Hofman, A. and Hunter, D.J. and Hveem, K. and Laakso, M. and Mohlke, K.L. and Morris, A.D. and Palmer, C.N.A. and Pramstaller, P.P. and Rudan, I. and Sijbrands, E. and Stein, L.D. and Tuomilehto, J. and Uitterlinden, A.G. and Wareham, N.J. and Watanabe, R.M. and Abecasis, G.R. and Boehm, B.O. and Campbell, H. and Daly, M.J. and Hattersley, A.T. and Hu, F.B. and Meigs, J.B. and Pankow, J.S. and Pedersen, O. and Wichmann, H.-E. and Barroso, I. and Groop, L. and Sladek, R. and Thorsteinsdottir, U. and Wilson, J.F. and Illig, T. and Froguel, P. and Van Duijn, C.M. and Stefansson, K. and Altshuler, D. and Boehnke, M. and McCarthy, M.I. and Speliotes, E.K. and Berndt, S.I. and Monda, K.L. and Allen, H.L. and Magi, R. and Randall, J.C. and Vedantam, S. and Winkler, T.W. and Workalemahu, T. and Heid, I.M. and Wood, A.R. and Weyant, R.J. and Estrada, K. and Liang, L. and Nemesh, J. and Park, J.-H. and Kilpelainen, T.O. and Yang, J. and Esko, T. and Feitosa, M.F. and Kutalik, Z. and Mangino, M. and Scherag, A. and Smith, A.V. and Zhao, J.H. and Aben, K.K. and Absher, D.M. and Dixon, A.L. and Fisher, E. and 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    journal = "Frontiers in Diabetes",
    year = "2011",
    volume = "60",
    number = "10",
    pages = "2624-2634",
    publisher = "American Diabetes Association Inc.",
    doi = "10.2337/db11-0415",
    keywords = "carrier protein;  glucose;  insulin;  membrane protein;  proinsulin;  proprotein convertase 1;  protein arap1;  protein larp6;  protein madd;  protein sgsm2;  protein slc30a8;  protein vps13c;  transcription factor 7 like 2;  unclassified drug, allele;  article;  cell function;  copy number variation;  coronary artery disease;  gene expression;  gene frequency;  gene locus;  gene mapping;  genetic association;  genetic heterogeneity;  genetic variability;  genotype;  glucose metabolism;  human;  meta analysis (topic);  non insulin dependent diabetes mellitus;  obesity;  pancreas islet beta cell;  pathophysiology;  priority journal;  quantitative trait;  signal transduction;  single nucleotide polymorphism",
    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. © 2011 by the American Diabetes Association."
}