Effects of rs7903146 Variation in the Tcf7l2 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，相关研究资料仍较为匮乏。研究方法与主要结果：我们在三个人群队列中探究了rs7903146位点对餐后脂代谢的影响，受试人群分别为健康年轻男性、代谢综合征（metabolic syndrome, MetS）患者及老年人群。88名健康男性受试者接受了单次富含饱和脂肪酸的试餐。此外，110名中年代谢综合征患者与20名≥65岁的健康老年人受试者，分别接受三种不同膳食模式干预后完成试餐试验。相较于其他基因型携带者，rs7903146的次要等位基因纯合子年轻男性受试者表现出更差的餐后血脂谱：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）水平呈升高趋势。在健康老年人群中，携带次要等位基因的受试者空腹状态下总胆固醇、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）胆固醇及小颗粒富含甘油三酯脂蛋白甘油三酯的曲线下面积均更高。上述结果伴随脂肪因子（adipokines）水平的差异性变化。本研究未观察到rs7903146位点对代谢综合征患者的餐后血脂状态存在任何影响。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群，其餐后脂代谢存在损伤，该损伤可能由脂肪因子调控异常介导，且与这类人群中观测到的更高心血管疾病风险相关。试验注册：ClinicalTrials.gov NCT00429195