Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.
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 beta-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 beta-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.
Cauchi
Stéphane
S
CNRS Institute of Biology, Pasteur Institute, Lille, France.
Meyre
David
D
Dina
Christian
C
Choquet
Hélène
H
Samson
Chantal
C
Gallina
Sophie
S
Balkau
Beverley
B
Charpentier
Guillaume
G
Pattou
François
F
Stetsyuk
Volodymyr
V
Scharfmann
Raphaël
R
Staels
Bart
B
Frühbeck
Gema
G
Froguel
Philippe
P
D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D051381:Rats; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C553059:Tcf7l2 protein, rat; D058118:Transcription Factor 7-Like 2 Protein