TY - JOUR
T1 - 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
AU - Yaghootkar, Hanieh
AU - Stancáková, Alena
AU - Freathy, Rachel M
AU - Vangipurapu, Jagadish
AU - Weedon, Michael N
AU - Xie, Weijia
AU - Wood, Andrew R
AU - Ferrannini, Ele
AU - Mari, Andrea
AU - Ring, Susan M
AU - Lawlor, Debbie A
AU - Davey Smith, George
AU - Jørgensen, Torben
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Steinthorsdottir, Valgerdur
AU - Guðbjartsson, Daniel F
AU - Thorleifsson, Gudmar
AU - Thorsteinsdottir, Unnur
AU - Stefansson, Kari
AU - Hattersley, Andrew T
AU - Walker, Mark
AU - Morris, Andrew D
AU - McCarthy, Mark I
AU - Palmer, Colin N A
AU - Laakso, Markku
AU - Frayling, Timothy M
N1 - © 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.
PY - 2015/6
Y1 - 2015/6
N2 - 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 3 10-13; 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 3 10-11; n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 3 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 3 10-9; n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m2; 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.
AB - 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 3 10-13; 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log10; P = 2 3 10-11; n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log10; P = 5 3 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 3 10-9; n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m2; 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.
KW - Alleles
KW - Body Mass Index
KW - Cyclin D2
KW - Diabetes Mellitus, Type 2
KW - Gene Frequency
KW - Genotype
KW - Humans
KW - Insulin
U2 - 10.2337/db14-1456
DO - 10.2337/db14-1456
M3 - Journal article
C2 - 25605810
SN - 0012-1797
VL - 64
SP - 2279
EP - 2285
JO - Diabetes
JF - Diabetes
IS - 6
ER -
