Table_1_Causal effects of genetically predicted type 2 diabetes mellitus on blood lipid profiles and concentration of particle-size-determined lipoprotein subclasses: A two-sample Mendelian randomization study.DOCX

BackgroundObservational studies have shown inconsistent results of the associations between type 2 diabetes mellitus (T2DM) and blood lipid profiles, while there is also a lack of evidence from randomized controlled trials (RCTs) for the causal effects of T2DM on blood lipid profiles and lipoprotein subclasses.ObjectivesOur study aimed at investigating the causal effects of T2DM on blood lipid profiles and concentration of particle-size-determined lipoprotein subclasses by using the two-sample Mendelian randomization (MR) method.MethodsWe obtained genetic variants for T2DM and blood lipid profiles including high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC) from international genome-wide association studies (GWASs). Two-sample MR method was applied to explore the potential causal effects of genetically predicted T2DM on blood lipid profiles based on different databases, respectively, and results from each MR analysis were further meta-analyzed to obtain the summary results. The causal effects of genetically predicted T2DM on the concentration of different subclasses of lipoproteins that are determined by particle size were also involved in MR analysis.ResultsGenetically predicted 1-unit higher log odds of T2DM had a significant causal effect on a higher level of TG (estimated β coefficient: 0.03, 95% confidence interval [CI]: 0.00 to 0.06) and lower level of HDL-C (estimated β coefficient: −0.09, 95% CI: −0.11 to −0.06). The causality of T2DM on the level of TC or LDL-C was not found (estimated β coefficient: −0.01, 95% CI: −0.02 to 0.01 for TC and estimated β coefficient: 0.01, 95% CI: −0.01 to 0.02 for LDL-C). For different sizes of lipoprotein particles, 1-unit higher log odds of T2DM was causally associated with higher level of small LDL particles, and lower level of medium HDL particles, large HDL particles, and very large HDL particles.ConclusionEvidence from our present study showed causal effects of T2DM on the level of TG, HDL-C, and concentration of different particle sizes of lipoprotein subclasses comprehensively, which might be particularly helpful in illustrating dyslipidemia experienced by patients with T2DM, and further indicate new treatment targets for these patients to prevent subsequent excessive cardiovascular events from a genetic point of view.

背景：观察性研究显示，2型糖尿病（T2DM）与血脂谱之间的关联结果并不一致，同时，随机对照试验（RCTs）对于T2DM对血脂谱和脂蛋白亚类因果效应的证据也缺乏。目标：本研究旨在利用双样本孟德尔随机化（MR）方法，探讨T2DM对血脂谱及由颗粒大小确定的脂蛋白亚类浓度的因果效应。方法：我们从国际全基因组关联研究（GWASs）中获取了T2DM和血脂谱的遗传变异，包括高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、甘油三酯（TG）和总胆固醇（TC）。分别基于不同数据库，应用双样本MR方法探究遗传预测的T2DM对血脂谱的潜在因果效应，并对每项MR分析的结果进行荟萃分析，以获得汇总结果。同时，将遗传预测的T2DM对由颗粒大小确定的脂蛋白不同亚类的浓度的影响也纳入MR分析。结果：遗传预测的T2DM每增加1单位的对数几率，对甘油三酯水平（估计β系数：0.03，95%置信区间[CI]：0.00至0.06）有显著的因果效应，并对高密度脂蛋白胆固醇水平（估计β系数：-0.09，95%CI：-0.11至-0.06）有降低效应。在TC或LDL-C水平上，未发现T2DM的因果效应（TC的估计β系数：-0.01，95%CI：-0.02至0.01；LDL-C的估计β系数：0.01，95%CI：-0.01至0.02）。对于不同大小的脂蛋白颗粒，T2DM每增加1单位的对数几率与较小LDL颗粒水平升高、中等HDL颗粒、大型HDL颗粒和超大型HDL颗粒水平降低具有因果关联。结论：本研究提供的证据全面显示了T2DM对甘油三酯、高密度脂蛋白胆固醇水平及脂蛋白亚类不同颗粒大小的浓度具有因果效应，这或许特别有助于阐释T2DM患者所经历的血脂异常，并进一步指出针对这些患者的新治疗靶点，从遗传学角度预防后续心血管事件的发生。