Effects of rs7903146 Variation in the <em>Tcf7l2</em> Gene in the Lipid Metabolism of Three Different Populations

BackgroundTCF7L2 rs7903146 is an important genetic factor predicting type 2 diabetes (T2DM) which has also been linked to higher cardiovascular risk. To date, there is little information about the additional impact of this single nucleotide polymorphism (SNP) beyond glucose metabolism. Methodology/Principal FindingsWe studied whether rs7903146 influenced postprandial lipid metabolism in three different populations (healthy young men, metabolic syndrome (MetS) patients and elderly persons). Eighty-eight healthy males were submitted to a single saturated fatty acid-rich test meal. Additionally, 110 middle-aged MetS patients and 20 healthy elderly persons (≥65 years) were submitted to three different dietary models followed by test meals. Minor allele homozygotes for rs7903146 showed a worse postprandial lipemia profile in young males, as seen by a lower HDL-cholesterol and Apo A1 concentration during the postprandial lipemia and a trend towards higher triglycerides (TG), than the other genotypes. In healthy elderly persons, carriers of the minor allele showed higher total cholesterol, LDL-cholesterol, Apo B and TG in the fasting state, and a higher postprandial area under the curve for total cholesterol, Apo B, small-triglyceride rich lipoprotein (TRL) cholesterol and small-(TRL) triglycerides. These results were accompanied by differential changes in adipokines. We did not observe any influence of rs7903146 on the postprandium of MetS patients. Conclusions/SignificanceHealthy young males and elderly persons who are carriers of the mutant allele for rs7903146 have an impaired postprandial lipid metabolism that may be mediated by an alteration in adipokine regulation, and may be related to the higher cardiovascular risk observed in these persons. Trial Registration ClinicalTrials.gov NCT00429195背景 TCF7L2基因rs7903146位点是预测2型糖尿病（type 2 diabetes, T2DM）的重要遗传因子，且该位点与更高的心血管疾病风险相关。截至目前，关于这一单核苷酸多态性（single nucleotide polymorphism, SNP）在葡萄糖代谢之外的额外影响，相关研究信息仍较为匮乏。 研究方法与主要结果 本研究纳入三个不同研究队列（健康年轻男性、代谢综合征（metabolic syndrome, MetS）患者及老年人），旨在探究rs7903146位点对餐后脂质代谢的影响。其中88名健康男性受试者接受单次富含饱和脂肪酸的标准试餐；另外110名中年代谢综合征患者与20名健康老年受试者（年龄≥65岁）则先后完成三种不同饮食模式干预后，再接受试餐检测。分析结果显示：相较于其他基因型携带者，年轻男性队列中rs7903146次要等位基因纯合子个体的餐后脂血症谱更差——餐后阶段高密度脂蛋白胆固醇（HDL-cholesterol）与载脂蛋白A1（Apo A1）浓度更低，且甘油三酯（triglycerides, TG）水平呈现升高趋势。在健康老年人群中，次要等位基因携带者的空腹总胆固醇、低密度脂蛋白胆固醇（LDL-cholesterol）、载脂蛋白B（Apo B）及甘油三酯水平均更高，且餐后总胆固醇、载脂蛋白B、小颗粒富含甘油三酯脂蛋白（small-triglyceride rich lipoprotein, TRL）胆固醇以及小颗粒富含甘油三酯脂蛋白甘油三酯的曲线下面积均显著升高。上述代谢异常伴随脂肪因子水平的差异性改变。本研究未观察到rs7903146位点对代谢综合征患者的餐后代谢状态存在任何影响。 结论与意义 携带rs7903146突变等位基因的健康年轻男性与老年人，其餐后脂质代谢存在损伤，该损伤可能由脂肪因子调控异常介导，且与这类人群中已观测到的更高心血管疾病风险存在关联。 试验注册 ClinicalTrials.gov 注册号：NCT00429195