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目的 通过孟德尔随机化(Mendelian randomization,MR)分析识别工具变量，以分析小而密低密度脂蛋白(Small dense low density lipoprotein,sdLDL)在冠状动脉粥样硬化性心脏病(Coronary heart disease,CHD，冠心病)病因中的因果作用。方法 在英国生物库(UK Biobank,UKBB)对低密度脂蛋白胆固醇(Low density lipoprotein cholesterol,LDL-C)、高密度脂蛋白胆固醇(High density lipoprotein cholesterol,HDL-C)、甘油三酯(Triacylglycerol,TG)和sdLDL的循环非空腹脂质特征进行全基因组关联研究(Genome-wide association study,GWAS)，以确定脂质相关的单核苷酸多态性(Single nucleotide polymorphism,SNP)。使用CARDIoGRAMplusC4D中的冠心病数据进行单变量和多变量MR分析。结果 GWAS确定了与LDL-C(n=220)、TG(n=440)、HDL-C(n=534)、sdLDL(n=440)在P<5×10-8时相关的多个独立SNP。单变量MR-逆方差加权(Inverse-varianceweighted,IVW)分析中，sd LDL(β=0.897)、HDL-C(β=-1.322)、LDL-C(β=0.881)和TG(β=0.420)均对CHD高风险存在显著影响(P<0.001)。在多变量MR分析中，只有sdLDL(β=0.813,P<0.001)保持了稳健的效果，LDL-C的影响作用被逆转(β=0.057,P=0.251),TG(β=0.221,P<0.001)和HDL-C(β=-0.048,P=0.011)的估计值被削弱。MR-Egger分析和MR-Lasso分析也显示出类似结果。通过Cochran's Q检验，MR-IVW(P=0.437)和MR-Egger回归分析(P=0.395)提示SNP之间不存在异质性。采用“留一法”进行敏感性分析，未发现对结果有显著影响的SNP，从而证实研究结果的可信度。结论 sdLDL是脂质与冠心病风险之间病因关系的主要特征分子之一，在解释脂质和冠心病风险的因果关系方面至关重要。
Abstract：Objective To identify instrumental variables using Mendelian randomization(MR) analysis and evaluate the causal role of small dense low-density lipoprotein(sdLDL) in the etiology of coronary heart disease(CHD). Methods A genome-wide association study(GWAS) was conducted at the UK Biobank(UKBB) for circulating non-fasting lipid profiles of low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), triglycerides(TG), and sdLDL to identify lipid-associated single nucleotide polymorphisms(SNPs). Univariate and multivariate MR analyses were performed using coronary heart disease data in CARDIoGRAMplusC4D. Results GWAS identified multiple independent SNPs associated with LDL-C(n=220), TG(n=440), HDL-C(n=534), sdLDL(n=440) at genome-wide significance(P<5×10-8). In univariate MR-Inverse-variance weighted(IVW) analysis, sdLDL(β=0.897), HDL-C(β=-1.322), LDL-C(β=0.881) and TG(β=0.420) had significant effects on the risk of CHD(P<0.001). In multivariate MR Analysis, only sdLDL(β=0.813; P<0.001) maintained a robust effect, and the effect of LDL-C was reversed(β=0.057; P=0.251), TG(β=0.221; P<0.001) and HDL-C(β=-0.048; P=0.011) had weakened estimates.. The MR-Egger analysis and MR-Lasso analysis also showed similar results. According to Cochran's Q test, there was no heterogeneity between SNPs in MR-IVW(P=0.437) and MR-Egger regression analysis(P=0.395). Sensitivity analysis using the leaveone-out approach showed that no SNP had a significant impact on the results, thereby confirming the robustness of the findings. Conclusion sdLDL is one of the main characteristic molecules of the etiological relationship between lipids and CHD risk, and is crucial in explaining the causal relationship between lipids and CHD risk.
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基本信息:
DOI：
中图分类号:R541.4
引用信息:
[1]潘金,白婷婷,丁礼丽等.小而密低密度脂蛋白与冠心病发生风险的因果关联：多变量孟德尔随机化分析[J].中国循证心血管医学杂志,2025,17(05):519-523.
基金信息:
陕西省科学技术研究发展计划支持项目(2011K12-60)