Mendelian randomization (MR) of lipid traits in coronary artery disease (CAD) has provided evidence for causal associations of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted (IVW) and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including body mass index (BMI), type 2 diabetes (T2D), and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, high-density lipoprotein cholesterol (HDL-C), TG, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TG suggests locus- and mechanism-specific causal effects of these factors on CAD.

中文翻译：

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冠状动脉疾病中的脂质和代谢综合征特征：孟德尔随机研究。


冠状动脉疾病 (CAD) 脂质性状的孟德尔随机化 (MR) 为低密度脂蛋白胆固醇 (LDL-C) 和甘油三酯 (TG) 在 CAD 中的因果关系提供了证据，但许多脂质性状遗传变异对 CAD 具有多效性影响。其他可能使 MR 关联产生偏差的心血管危险因素。本研究的目的是评估脂质性状遗传变异的多效性效应，并在 CAD 脂质性状 MR 中解释这些效应。我们使用逆方差加权 (IVW) 和 MR-Egger 方法在大型 (n ≥ 300,000) GWAS 数据集中执行多变量 MR。我们发现，30% 的脂质性状遗传变异对代谢综合征性状有影响，包括体重指数 (BMI)、2 型糖尿病 (T2D) 和收缩压 (SBP)。尽管如此，在多变量 MR 分析中，LDL-C、高密度脂蛋白胆固醇 (HDL-C)、TG、BMI、T2D 和 SBP 与 CAD 独立相关，并且这些关联中的每一个对于定向多效性的调整都是稳健的。与 HDL-C 和 TG 直接影响相关的基因座 MR 表明这些因素对 CAD 具有基因座特异性和机制特异性因果效应。