A variant in CDKAL1 influences insulin response and risk of type 2 diabetes

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Valgerdur Steinthorsdottir, Gudmar Thorleifsson, Inga Reynisdottir, Rafn Benediktsson, Thorbjorg Jonsdottir, G Bragi Walters, Unnur Styrkarsdottir, Solveig Gretarsdottir, Valur Emilsson, Shyamali Ghosh, Adam Baker, Steinunn Snorradottir, Hjordis Bjarnason, Maggie C Y Ng, Torben Hansen, Yu Bagger, Robert L Wilensky, Muredach P Reilly, Adebowale Adeyemo, Yuanxiu Chen & 25 others Jie Zhou, Vilmundur Gudnason, Guanjie Chen, Hanxia Huang, Kerrie Lashley, Ayo Doumatey, Wing-Yee So, Ronald C Y Ma, Gitte Andersen, Knut Borch-Johnsen, Torben Jorgensen, Jana V van Vliet-Ostaptchouk, Marten H Hofker, Cisca Wijmenga, Claus Christiansen, Daniel J Rader, Charles Rotimi, Mark Gurney, Juliana C N Chan, Oluf Pedersen, Gunnar Sigurdsson, Jeffrey R Gulcher, Unnur Thorsteinsdottir, Augustine Kong, Kari Stefansson

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.
Original languageEnglish
JournalNature Genetics
Volume39
Issue number6
Pages (from-to)770-5
Number of pages6
ISSN1061-4036
DOIs
Publication statusPublished - 2007

    Research areas

  • Adult, Blood Glucose, Carrier Proteins, Case-Control Studies, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Gene Frequency, Genome, Human, Humans, Insulin, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Linkage Disequilibrium, Male, Middle Aged, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, TCF Transcription Factors, Transcription Factor 7-Like 1 Protein, Transcription Factor 7-Like 2 Protein

ID: 38455034