Common SNPs in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in non-diabetic individuals. R. Saxena^1,2, L. Gianniny², N. Burtt², V. Lyssenko³, C. Giuducci², M. Sjögren³, J. Florez^1,2, P. Almgren³, B. Isomaa⁴, M. Orho-Melander³, U. Lindblad^3,5, M. Daly^1,2, T. Tuomi⁴, J.N. Hirschhorn^2,6,7, K. Ardlie^2,8, L. Groop⁴, D. Altshuler^1,2,7. 1) Massachusetts General Hospital, Boston, MA; 2) Broad Institute of Harvard and MIT, Cambridge, MA; 3) Lund University, Malmö, Sweden; 4) University of Helsinki, Helsinki, Finland; 5) Skaraborg Institute, Skövde, Sweden; 6) Childrens Hospital, Boston, MA; 7) Harvard Medical School, Boston, MA; 8) Genomics Collaborative Inc., Cambridge, MA.
   Recently, common non-coding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark and the US. We genotyped 13 SNPs across TCF7L2 in 8,310 individuals in family based and case-control designs from Scandinavia, Poland and the US. We convincingly confirmed the previous association of TCF7L2 SNPs with risk of type 2 diabetes (rs7903146T OR 1.40 (95% CI 1.30 - 1.50); P = 6.74 x 10^-20). In non-diabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of non-carriers; P = 0.003), but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase risk of type 2 diabetes.