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

Struan F A Grant¹, Gudmar Thorleifsson¹, Inga Reynisdottir¹, Rafn Benediktsson^2, 3, Andrei Manolescu¹, Jesus Sainz¹, Agnar Helgason¹, Hreinn Stefansson¹, Valur Emilsson¹, Anna Helgadottir¹, Unnur Styrkarsdottir¹, Kristinn P Magnusson¹, G Bragi Walters¹, Ebba Palsdottir¹, Thorbjorg Jonsdottir¹, Thorunn Gudmundsdottir¹, Arnaldur Gylfason¹, Jona Saemundsdottir¹, Robert L Wilensky⁴, Muredach P Reilly⁴, Daniel J Rader⁴, Yu Bagger⁵, Claus Christiansen⁵, Vilmundur Gudnason², Gunnar Sigurdsson^2, 3, Unnur Thorsteinsdottir¹, Jeffrey R Gulcher¹, Augustine Kong¹ & Kari Stefansson¹

¹  deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.

²  Icelandic Heart Association, 201 Kopavogur, Iceland.

³  National University Hospital, 108 Reykjavik, Iceland.

⁴  University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 USA.

⁵  Center for Clinical and Basic Research A/S, 2750 Ballerup, Denmark.

NM_030756We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q¹. 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 10^-9). This was replicated in a Danish cohort (P = 4.8 10^-3) and in a US cohort (P = 3.3 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 pathway².

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