A variant in CDKAL1 influences insulin response and risk of type 2 diabetes by Steinthorsdottir Valgerdur, Thorleifsson Gudmar, Reynisdottir Inga, Benediktsson Rafn, Jonsdottir Thorbjorg, Walters G Bragi, Styrkarsdottir Unnur, Gretarsdottir Solveig, Emilsson Valur, Ghosh Shyamali, Baker Adam, Snorradottir Steinunn, Bjarnason Hjordis, Ng Maggie C Y, Hansen Torben, Bagger Yu, Wilensky Robert L, Reilly Muredach P, Adeyemo Adebowale, Chen Yuanxiu, Zhou Jie, Gudnason Vilmundur, Chen Guanjie, Huang Hanxia, Lashley Kerrie, Doumatey Ayo, So Wing-Yee, Ma Ronald C Y, Andersen Gitte, Borch-Johnsen Knut, Jorgensen Torben, van Vliet-Ostaptchouk Jana V, Hofker Marten H, Wijmenga Cisca, Christiansen Claus, Rader Daniel J, Rotimi Charles, Gurney Mark, Chan Juliana C N, Pedersen Oluf, Sigurdsson Gunnar, Gulcher Jeffrey R, Thorsteinsdottir Unnur, Kong Augustine, Stefansson Kari in Nature genetics (2007). PubMed

Abstract

We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

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