Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes

Struan F A Grant, Gudmar Thorleifsson, Inga Reynisdottir, Rafn Benediktsson, Andrei Manolescu, Jesus Sainz, Agnar Helgason, Hreinn Stefansson, Valur Emilsson, Anna Helgadottir, Unnur Styrkarsdottir, Kristinn P Magnusson, G Bragi Walters, Ebba Palsdottir, Thorbjorg Jonsdottir, Thorunn Gudmundsdottir, Arnaldur Gylfason, Jona Saemundsdottir, Robert L Wilensky, Muredach P Reilly, Daniel J Rader, Yu Bagger, Claus Christiansen, Vilmundur Gudnason, Gunnar Sigurdsson, Unnur Thorsteinsdottir, Jeffrey R Gulcher, Augustine Kong, Kari Stefansson
Nature Genetics 2006, 38 (3): 320-3
We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.

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