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

被引:22
作者
Yaghootkar, Hanieh [1 ]
Stancakova, Alena [2 ]
Freathy, Rachel M. [1 ]
Vangipurapu, Jagadish [2 ]
Weedon, Michael N. [1 ]
Xie, Weijia [1 ]
Wood, Andrew R. [1 ]
Ferrannini, Ele [3 ]
Mari, Andrea [4 ]
Ring, Susan M. [5 ,6 ]
Lawlor, Debbie A. [5 ,6 ]
Smith, George Davey [5 ,6 ]
Jorgensen, Torben [7 ,8 ]
Hansen, Torben [9 ,10 ]
Pedersen, Oluf [9 ]
Steinthorsdottir, Valgerdur [11 ]
Gudbjartsson, Daniel F. [11 ,12 ]
Thorleifsson, Gudmar [11 ]
Thorsteinsdottir, Unnur [11 ,13 ]
Stefanssonn, Kari [11 ,13 ]
Hattersley, Andrew T. [14 ]
Walker, Mark [15 ]
Morris, Andrew D. [16 ]
McCarthy, Mark I. [17 ,18 ,19 ]
Palmer, Colin N. A. [16 ]
Laakso, Markku [2 ,20 ]
Frayling, Timothy M. [1 ]
机构
[1] Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England
[2] Univ Eastern Finland, Kuopio, Finland
[3] CNR Inst Clin Physiol, Pisa, Italy
[4] CNR Inst Biomed Engn, Padua, Italy
[5] Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol, Avon, England
[6] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England
[7] Glostrup Univ Hosp, Res Ctr Prevent & Hlth, Glostrup, Denmark
[8] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark
[9] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark
[10] Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark
[11] Amgen Inc, deCODE Genet, Reykjavik, Iceland
[12] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland
[13] Univ Iceland, Fac Med, Reykjavik, Iceland
[14] Univ Exeter, Sch Med, Genet Diabet, Exeter, Devon, England
[15] Newcastle Univ, Sch Med, Inst Cellular Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England
[16] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee DD1 9SY, Scotland
[17] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England
[18] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England
[19] Churchill Hosp, Natl Inst Hlth Res, Oxford Biomed Res Ctr, Oxford OX3 7LJ, England
[20] Kuopio Univ Hosp, Dept Med, SF-70210 Kuopio, Finland
基金
英国惠康基金; 欧洲研究理事会; 芬兰科学院;
关键词
SENSITIVITY;
D O I
10.2337/db14-1456
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 x 10(-13); 6,647 case vs. 12,645 control subjects), higher disposition index (beta = 0.07 log10; P = 2 x 10(-11); n = 13,028), and higher Matsuda index of insulin sensitivity (beta = 0.02 10g10; P = 5 x 10(-3); n = 13,118) but not fasting proinsulin (beta = 0.01 log10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (beta = 1.38 cm; P = 6 x 10(-9) n = 13,927), but the association of the variant with BMI (beta = 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.
引用
收藏
页码:2279 / 2285
页数:7
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