Stolerman E S, Manning A K, McAteer J B, Fox C S, Dupuis J, Meigs J B, Florez J C
Simches Research Building-CPZN 5.250, Diabetes Unit/Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, 02114, USA.
Diabetologia. 2009 Apr;52(4):614-20. doi: 10.1007/s00125-009-1266-2. Epub 2009 Jan 31.
AIMS/HYPOTHESIS: Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS).
We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures.
As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 x 10(-7)) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92).
CONCLUSIONS/INTERPRETATION: We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls.
目的/假设:TCF7L2基因的常见变异通过损害胰岛素分泌与2型糖尿病相关。一种假设是TCF7L2的变异会损害β细胞中的胰岛素加工过程。相比之下,相关的TCF7L2多态性与肥胖的关联存在争议,因为仅在易受确定偏倚影响的队列中得到证实。我们在弗雷明汉心脏研究(FHS)中重现了糖尿病相关变异与胰岛素原/胰岛素比值的关联,并研究了TCF7L2单倍型与肥胖的关联。
我们对2512名FHS参与者的TCF7L2单核苷酸多态性rs7903146和rs12255372(先前与2型糖尿病相关)以及rs10885406和rs7924080(标记单倍型A [HapA],一种据报道与肥胖相关的单倍型)进行基因分型。我们使用年龄和性别调整的线性混合效应模型来测试与血糖特征胰岛素原/胰岛素比值和肥胖指标的关联。
正如预期的那样,rs7903146的T风险等位基因与较高空腹血糖相关(p = 0.01)。与C/C纯合子相比,T/T纯合子的胰岛素原/胰岛素比值增加23.5%(p = 1×10^(-7))。HapA与体重指数(p = 0.98)、腰围(p = 0.89)、皮下脂肪组织(p = 0.32)或内脏脂肪组织(p = 0.92)均无关联。
结论/解读:我们证实rs7903146的风险等位基因与高血糖和较高的胰岛素原/胰岛素比值相关。我们未检测到TCF7L2 HapA与肥胖指标之间存在任何关联,这表明这可能是由确定偏倚导致的虚假关联,可能是由于在血糖病例和对照的不同组中评估肥胖所引起的。