Background Type 2 diabetes mellitus (T2DM) and obesity are complex pandemic diseases in the 21st century. Worldwide, the T allele rs7903146 in the TCF7L2 gene is recognized as a strong GWAS signal associated with T2DM. However, the association between the C allele and obesity is still poorly explored and needs to be replicated in other populations. Thus, the primary objectives of this study were to evaluate the TCF7L2 rs7903146 association with T2DM according to BMI status and to determine if this variant is related to obesity and BMI variation in a cohort of elderly Brazilians. Methods A total of 1,023 participants from an elderly census-based cohort called SABE (Saúde, Bem Estar e Envelhecimento—Health, Well-Being and Aging) were stratified by BMI status and type 2 diabetes presence. The TCF7L2 genotypes were filtered from the Online Archive of Brazilian Mutations (ABraOM—Online Archive of Brazilian Mutations) database, a web-based public database with sequencing data of samples of the SABE’s participants. Logistic regression models and interaction analyses were performed. The BMI variation (∆BMI) was calculated from anthropometric data collected in up to two time-points with a ten-year-assessment interval. Results The association between the rs7903146 T allele and T2DM was inversely proportional to the BMI status, with an increased risk in the normal weight group (OR 3.36; 95% CI [1.46–7.74]; P = 0.004). We confirmed the T allele association with risk for T2DM after adjusting for possible confound ing variables (OR 2.35; 95% CI [1.28–4.32]; P = 0.006). Interaction analysis showed that the increased risk for T2DM conferred by the T allele is modified by BMI (Pinteraction = 0.008), age (Pinteraction = 0.005) and gender (Pinteraction = 0.026). A T allele protective effect against obesity was observed (OR 0.71; 95% CI [0.54–0.94]; P = 0.016). The C allele increased obesity risk (OR 1.40; 95% CI [1.06–1.84]; P = 0.017) and the CC genotype showed a borderline association with abdominal obesity risk (OR 1.28; 95% CI [1.06–1.67]; P = 0.045). The CC genotype increased the obesity risk factor after adjusting for possible confounding variables (OR 1.41; 95% CI [1.06–1.86]; P = 0.017). An increase of the TT genotype in the second tertile of ∆BMI values was observed in participants without type 2 diabetes (OR 5.13; 95% CI [1.40–18.93]; P = 0.009) in the recessive genetic model. Conclusion We confirmed that the rs7903146 is both associated with T2DM and obesity. The TCF7L2 rs7903146 T allele increased T2DM risk in the normal weight group and interacted with sex, age and BMI, while the C allele increased obesity risk. The TT genotype was associated with a lesser extent of BMI variation over the SABE study’s 10-year period.

中文翻译：

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巴西老年队列中 TCF7L2 rs7903146 多态性与糖尿病和肥胖的关联

背景 2 型糖尿病 (T2DM) 和肥胖症是 21 世纪复杂的流行病。在世界范围内，TCF7L2 基因中的 T 等位基因 rs7903146 被认为是与 T2DM 相关的强 GWAS 信号。然而，C 等位基因与肥胖之间的关联仍然没有得到很好的探索，需要在其他人群中进行复制。因此，本研究的主要目标是根据 BMI 状态评估 TCF7L2 rs7903146 与 T2DM 的关联，并确定该变异是否与巴西老年人群中的肥胖和 BMI 变异有关。方法 共有 1,023 名来自名为 SABE（Saúde、Bem Estar e Envelhecimento-Health、Well-Being and Aging）的老年人口普查队列的参与者按 BMI 状态和 2 型糖尿病的存在进行分层。TCF7L2 基因型是从巴西突变在线档案（ABraOM-巴西突变在线档案）数据库中过滤出来的，这是一个基于网络的公共数据库，其中包含 SABE 参与者样本的测序数据。进行了逻辑回归模型和交互分析。BMI 变化 (ΔBMI) 是根据以十年评估间隔在最多两个时间点收集的人体测量数据计算的。结果 rs7903146 T 等位基因与 T2DM 之间的关联与 BMI 状态成反比，正常体重组的风险增加（OR 3.36；95% CI [1.46–7.74]；P = 0.004）。在调整可能的混杂变量后，我们证实了 T 等位基因与 T2DM 风险的关联（OR 2.35；95% CI [1.28–4.32]；P = 0.006）。相互作用分析表明，T 等位基因导致的 T2DM 风险增加受 BMI（Pinteraction = 0.008）、年龄（Pinteraction = 0.005）和性别（Pinteraction = 0.026）的影响。观察到 AT 等位基因对肥胖的保护作用（OR 0.71；95% CI [0.54-0.94]；P = 0.016）。C 等位基因增加肥胖风险（OR 1.40；95% CI [1.06-1.84]；P = 0.017），CC 基因型与腹部肥胖风险呈临界关联（OR 1.28；95% CI [1.06-1.67]；P = 0.045)。在调整可能的混杂变量后，CC 基因型增加了肥胖风险因素（OR 1.41；95% CI [1.06–1.86]；P = 0.017）。在隐性遗传模型中，在没有 2 型糖尿病的参与者中观察到 ΔBMI 值的第二个三分位数的 TT 基因型增加（OR 5.13；95% CI [1.40–18.93]；P = 0.009）。结论 我们证实 rs7903146 与 T2DM 和肥胖有关。TCF7L2 rs7903146 T 等位基因增加了正常体重组的 T2DM 风险，并与性别、年龄和 BMI 相互作用，而 C 等位基因增加了肥胖风险。在 SABE 研究的 10 年期间，TT 基因型与较小程度的 BMI 变异相关。