TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program
TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program
复制标题
DOI：
10.1056/nejmoa062418
复制
发表时间：
2006-07-20
影响因子：
158.5
通讯作者：
Altshuler, David
中科院分区：
文献类型：
--
作者：
Florez, Jose C.;Jablonski, Kathleen A.;Altshuler, David
背景：转录因子7样2基因（TCF 7 L2）的常见多态性最近被认为与2型糖尿病相关。我们研究了两个最紧密相关的变体（rs 12255372和rs7903146）预测参加糖尿病预防计划的糖耐量受损患者的糖尿病进展，其中生活方式干预或二甲双胍治疗与安慰剂进行比较。我们对3548名受试者的这些变异进行了基因分型，并使用基因型、干预及其相互作用作为预测因子进行了考克斯回归分析。我们评估了基因型对基线和1年时胰岛素分泌和胰岛素敏感性指标的影响。结果：在平均3年的时间内，rs7903146位点TT基因型的参与者比CC纯合子更有可能从糖耐量受损进展为糖尿病（风险比，1.55; 95%置信区间，1.20至2.01; P < 0.001）。安慰剂组中基因型的影响（风险比，1.81; 95%置信区间，1.21 - 2.70; P=0.004）强于二甲双胍组和生活方式干预组（风险比，分别为1.62和1.15;基因型和干预之间的相互作用P不显著）。TT基因型与基线时胰岛素分泌减少相关，但与胰岛素抵抗增加无关。rs 12255372也获得了类似的结果。结论：TCF 7 L2基因的常见变异可能与糖耐量受损人群中糖尿病风险的增加有关。TCF 7 L2中的风险基因型与β细胞功能受损相关，但与胰岛素抵抗无关。（ClinicalTrials.gov编号，NTC 00004992。）
Background: Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo.Methods: We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year.Results: Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P < 0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372.Conclusions: Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NTC00004992.)