Cauchi Stéphane, Choquet Hélène, Gutiérrez-Aguilar Ruth, Capel Frédéric, Grau Katrine, Proença Christine, Dina Christian, Duval Alex, Balkau Beverley, Marre Michel, Potoczna Natascha, Langin Dominique, Horber Fritz, Sørensen Thorkild I A, Charpentier Guillaume, Meyre David, Froguel Philippe
Centre National de la Recherche Scientifique 8090, Institute of Biology, Pasteur Institute, Lille, France.
Obesity (Silver Spring). 2008 Feb;16(2):476-82. doi: 10.1038/oby.2007.77.
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.
转录因子7样2（TCF7L2）基因的rs7903146 T等位基因先前与2型糖尿病（T2D）相关，且与体重指数（BMI）降低有关，而携带rs7903146 C和rs10885406 A等位基因的单倍型（单倍型A）与BMI升高有关。TCF7L2基因多态性的功能相关性及其对T2D和肥胖症的影响仍有待进一步研究。在欧洲白人人群中，我们发现，rs7903146 T等位基因在3547名非肥胖个体中与T2D的关联更强（优势比（OR）=1.88（1.69 - 2.10）），而在1110名III级肥胖受试者中关联较弱（OR = 1.24（1.03 - 1.50））。在3507名糖耐量正常（NGT）个体、1106个有家族性肥胖的家系以及来自法国普通人群的5512名个体中，未发现rs7903146 C等位基因和单倍型A对任何形式的肥胖症有直接影响。然而，在T2D受试者中，rs7903146 C等位基因在1111名非肥胖个体中的流行率（55.2%）低于659名III级肥胖受试者（67.5%，OR = 1.69（1.46 - 1.95））。功能研究表明，在3T3 - L1、HepG2和β - TC3细胞系中，rs7903146 T等位基因比C等位基因更不易被蛋白质因子结合，并且在热量限制下，NGT肥胖T/T携带者皮下脂肪组织中的TCF7L2表达降低。总之，在欧洲人群中，TCF7L2不是肥胖症的危险因素，但其对T2D风险的影响受肥胖症调节。此外，我们的数据表明，rs7903146 T等位基因可能具有功能，并且与热量限制下个体脂肪组织中TCF7L2表达的名义降低有关。
