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Transcription Factor TCF7L2 Genetic Study in the French Population

Expression in Human ß-Cells and Adipose Tissue and Strong Association With Type 2 Diabetes

¹ CNRS 8090 Institute of Biology, Pasteur Institute, Lille, France
² INSERM U780-IFR69, Villejuif, France
³ Corbeil Hospital, Corbeil, France
⁴ INSERM ERIT-M 0106, Lille, France
⁵ Necker Hospital, INSERM E363, Paris, France
⁶ Atherosclerosis Department, Pasteur Institute, Lille, France
⁷ INSERM U545, Lille, France
⁸ University of Lille 2, Lille, France
⁹ Department of Metabolic Research, Clinica Universitaria de Navarra, Pamplona, Spain
¹⁰ Section of Genomic Medicine, Hammersmith Hospital, Imperial College, London, U.K

Address correspondence and reprint requests to Philippe Froguel, Imperial College, Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, U.K. E-mail: p.froguel{at}imperial.ac.uk

Abbreviations: FBAT, family-based association test; GLP-1, glucagon-like peptide 1; PAR, population-attributable risk; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test

Recently, the transcription factor 7-like 2 (TCF7L2) gene has been associated with type 2 diabetes in subjects of European origin in the DeCode study. We genotyped the two most associated variants (rs7903146 and rs12255372) in 2,367 French type 2 diabetic subjects and in 2,499 control subjects. Both the T-allele of rs7903146 and the T-allele of rs12255372 significantly increase type 2 diabetes risk with an allelic odds ratio (OR) of 1.69 (95% CI 1.55–1.83) (P = 6.0 x 10^–35) and 1.60 (1.47–1.74) (P = 7.6 x 10^–28), respectively. In nonobese type 2 diabetic subjects (BMI <30 kg/m², n = 1,346), the ORs increased to 1.89 (1.72–2.09) (P = 2.1 x 10^–38) and 1.79 (1.62–1.97) (P = 5.7 x 10^–31), respectively. The rs7903146 T at-risk allele associates with decreased BMI and earlier age at diagnosis in the type 2 diabetic subjects (P = 8.0 x 10^–3 and P = 3.8 x 10^–4, respectively), which is supported by quantitative family-based association tests. TCF7L2 is expressed in most human tissues, including mature pancreatic ß-cells, with the exception of the skeletal muscle. In the subcutaneous and omental fat from obese type 2 diabetic subjects, TCF7L2 expression significantly decreased compared with obese normoglycemic individuals. During rat fetal ß-cell differentiation, TCF7L2 expression pattern mimics the key marker NGN3 (neurogenin 3), suggesting a role in islet development. These data provide evidence that TCF7L2 is a major determinant of type 2 diabetes risk in European populations and suggests that this transcription factor plays a key role in glucose homeostasis.

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