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Nature Genetics 38, 320 - 323 (2006)
Published online: 15 January 2006; | doi:10.1038/ng1732

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

Struan F A Grant1, Gudmar Thorleifsson1, Inga Reynisdottir1, Rafn Benediktsson2, 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 Sigurdsson2, 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.

Correspondence should be addressed to Struan F A Grant or Kari Stefansson

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 times 10-9). This was replicated in a Danish cohort (P = 4.8 times 10-3) and in a US cohort (P = 3.3 times 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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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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