title: Effects of TCF7L2 polymorphisms on obesity in European populations.
abstract: The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated. In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction. In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.
authors.affiliation: Centre National de la Recherche Scientifique 8090, Institute of Biology, Pasteur Institute, Lille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.forename: Hélène
authors.initials: H
authors.lastname: Choquet
authors.forename: Ruth
authors.initials: R
authors.lastname: Gutiérrez-Aguilar
authors.forename: Frédéric
authors.initials: F
authors.lastname: Capel
authors.forename: Katrine
authors.initials: K
authors.lastname: Grau
authors.forename: Christine
authors.initials: C
authors.lastname: Proença
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Alex
authors.initials: A
authors.lastname: Duval
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Natascha
authors.initials: N
authors.lastname: Potoczna
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.forename: Fritz
authors.initials: F
authors.lastname: Horber
authors.forename: Thorkild I A
authors.initials: TI
authors.lastname: Sørensen
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D015992:Body Mass Index; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000209:etiology; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D050151:Subcutaneous Fat / Q000378:metabolism; D051820:TCF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D044465:White People / Q000208:ethnology / Q000235:genetics
chemical_list: D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein