Association analysis of 29,956 individuals confirms that a low-frequency variant at CCND2 halves the risk of type 2 diabetes by enhancing insulin secretion.
Weedon, Michael N.
Davey Smith, G
Hattersley, Andrew T.
McCarthy, Mark I.
Frayling, Timothy M.
American Diabetes Association
Copyright © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P = 2 × 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 × 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 × 10(-3); n = 13,118) but not fasting proinsulin (β = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β = 1.38 cm; P = 6 × 10(-9); n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m(2); P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion.
Academy of Finland
University of Eastern Finland
Sigrid Juselius Foundation
University of Bristol (ALSPAC)
Novo Nordisk Foundation Center for Basic Metabolic Research
Danish Agency for Science, Technology and Innovation
PhD School of Molecular Metabolism
University of Southern Denmark
Copenhagen Graduate School of Health and Medical Sciences
Danish Research Council
Danish Centre for Health Technology Assessment
Research Foundation of Copenhagen County
Ministry of Internal Affairs and Health
Danish Heart Foundation
Ib Henriksen Foundation
Research Support, Non-U.S. Gov't
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This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db14-1456/-/DC1.
Vol. 64, no. 6, pp. 2279 - 2285
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