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- Title
Variation in TCF7L2 Influences Glycemic Response to Sulfonylureas.
- Authors
Pearson, Ewan R.; Donnelly, Louise; Doney, Alex; Hattersley, Andrew T.; Mccarthy, Mark I.; Morris, Andrew D.; Palmer, Colin N.
- Abstract
Common variation in the Transcription factor 7-like 2 gene (TCF7L2) is strongly associated with type 2 diabetes. The function of TCF7L2 is poorly understood although some data suggests a role in beta-cell function. As sulfonylureas stimulate beta-cells we hypothesised that variation in TCF7L2 will influence glycemic response to sulfonylureas, but not to mefformin. Two independent data sets were used: GoDARTS1 (GD1) and the Wellcome Trust UK Type 2 diabetes case control consortium (GD2). Incident users of sulfonylureas (GD1 n=359; GD2 n=588) and metformin (GD1 n=253; GD2 n=735) with type 2 diabetes and HbA1c data 3-12 months from starting treatment between 1993 and 2004 were identified, and genotyped at TCF7L2 rs12255372. In GD1, only 36% of TT homozygotes were treated to a target hba1c <7% with sulfonylureas compared to 62% of G* (GT/GG) individuals (OR 0.35, p=0.003). In GD2, the equivalent OR was 0.65, p=0.1. Combining GD1 and GD2 gave an OR of 0.52, p=0.002. In the combined data set, a logistic regression model was used with the covariates: age of diabetes diagnosis, sex, bmi, diabetes duration and drug dose. In this model the OR for treatment success (TT vs G*) was 0.49, p=0.001, and this remained significant (OR 0.48, p=0.008) with addition of pre-treatment HbA1c to the model (n=515). By contrast in a similar model there was no effect of TCF7L2 genotype on metformin response (logistic regression OR 0.95, p=0.86). We conclude that variation in TCF7L2 predicts treatment response to sulfonylureas but not to metformin. This is a robust example of pharmacogenetics within a large Type 2 diabetic population.
- Subjects
GENES; TRANSCRIPTION factors; GLUCOSE; HYPOGLYCEMIC agents; PHARMACOGENOMICS; TYPE 2 diabetes
- Publication
Diabetes, 2007, Vol 56, pA18
- ISSN
0012-1797
- Publication type
Article