A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

Andrew R Wood, Anna Jonsson, Anne U. Jackson, Nan Wang, Nienke van Leewen, Nicholette D. Palmer, Sayuko Kobes, Joris Deelen, Lorena Boquete-Vilarino, Jussi Paananen, Alena Stančáková, Dorret I. Boomsma, Eco J. C. de Geus, Elisabeth M. W. Eekhoff, Andreas Fritsche, Mark H. H. Kramer, Giel Nijpels, Annemarie M. C. Simonis-Bik, Timon W. van Haeften, Anubha MahajanMichael Boehnke, Richard N. Bergman, Jaakko Tuomilehto, Francis S. Collins, Karen L. Mohlke, Karina Banasik, Christopher J. Groves, Mark I. McCarthy, Ewan R Pearson, Andrea Natali, Andrea Mari, Thomas A. Buchanan, Kent D. Taylor, Anny H Xiang, Anette P. Gjesing, Niels Grarup, Hans Eiberg, Oluf Pedersen, Yii-Derr Chen, Markku Laakso, Jill M. Norris, Ulf Smith, Lynne E. Wagenknecht, Leslie Baier, Donald W. Bowden (Lead / Corresponding author), Torben Hansen (Lead / Corresponding author), Mark Walker (Lead / Corresponding author), Richard M. Watanabe (Lead / Corresponding author), Leen M. 't Hart (Lead / Corresponding author), Robert L. Hanson (Lead / Corresponding author), Timothy M. Frayling (Lead / Corresponding author)

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Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 non-diabetic individuals from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycaemic traits and identify new loci. Thirty type 2 diabetes, or fasting glucose raising, alleles were associated with a measure of first phase insulin secretion at P<0.05, and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGFBP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1 and TMPRSS6 loci. The fasting glucose raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycaemic traits.
Original languageEnglish
Pages (from-to)2296-2309
Number of pages14
Issue number8
Early online date10 May 2017
Publication statusPublished - 21 Jul 2017


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