基于孟德尔随机化方法探讨脂质和降脂药物与慢性阻塞性肺病的遗传关联

doi:10.6040/j.issn.1671-7554.0.2024.0159

摘要/Abstract

摘要： 目的采用孟德尔随机化分析方法(Mendelian randomization, MR)从遗传学角度探讨脂质性状在慢性阻塞性肺病(chronic obstructive pulmonary disease, COPD)中的因果作用,并评估降脂药物靶点对COPD的潜在影响。方法从全球脂质遗传学联盟(the Global Lipids Genetics Consortium, GLGC)和表达型数量性状位点基因组联盟(Expressed Quantitative Trait Loci Genome Consortium, eQTLGen Consortium)中提取了与脂质性状相关的遗传变异和降脂药物靶标的编码基因变异。其中脂质性状和降脂药物靶标作为暴露变量,分别来自GLGC和eQTLGen Consortium;COPD作为结局变量,来自芬兰数据库(https://doi.org/10.1038/s41586-022-05473-8)。将与暴露变量强相关的单核苷酸多态性(single nucleotide polymorphisms,SNP)作为工具变量,采用逆方差加权法(inverse-variance weighted, IVW)作为主要分析方法探索脂质性状在COPD中的因果作用及降脂药物靶点对COPD的潜在影响,MR-Egger回归法和加权中位数法(weighted median, WME)作为IVW结果的补充证据,采用留一法敏感性分析探讨单个SNP对IVW分析结果的影响,同时采用MR-Egger法的截距和Cochrans Q检验进行水平多效性和异质性的检验保证结果的稳定性,采用漏斗图分析研究结果的潜在偏倚情况。对于达到COPD风险显著性的药物靶点CETP,共定位分析用于检验排除限制假设。结果 IVW法分析结果显示,LDL-C(OR=1.077,95%CI:1.001~1.159,P=0.046)和TC(OR=1.088,95%CI:1.002~1.181,P=0.044)遗传水平的增加与COPD风险增加相关。CETP遗传水平的增加与COPD风险增加相关(OR=1.179,95%CI:1.052~1.321,P=0.004)。MR-Egger回归、Cochrans Q检验、留一法均提示研究结果具有可靠性和稳健性。结论血脂异常是COPD的致病因素。LDL-C和TC水平的增加与COPD的发病有关,在3个降脂药物靶点中,CETP是COPD有前途的候选药物靶点。

关键词: 孟德尔随机化, 他汀类药物, 总胆固醇, 甘油三酯, 低密度脂蛋白, 高密度脂蛋白

Abstract: Objective To explore the causal role of lipid traits in chronic obstructive pulmonary disease(COPD)from a genetic perspective and to evaluate the potential impact of lipid-lowering medication targets on COPD by using Mendelian randomization(MR)analysis. Methods Genetic variants associated with lipid traits and genetic variants coding for lipid-lowering drug targets were extracted from The Global Lipids Genetics Consortium(GLGC)and the Expressed Quantitative Trait Loci Genome Consortium(eQTLGen Consortium). Lipid traits and lipid-lowering drug targets were extracted from GLGC and eQTLGen Consortium as exposure variables, and COPD was derived from the FinnGen database(https://www.finngen.fi/en)as the outcome variable. Single nucleotide polymorphism(SNP)strongly associated with the exposure variables were used as instrumental variables, and the inverse variance weighted(IVW)was used as the main method to explore the the causal role of lipid traits in COPD and the potential effects of lipid-lowering drug targets on COPD, MR-Egger regression and the weighted median was used as complementary evidence to the IVW results. A Leave-one-out sensitivity analysis was used to explore the effect of individual SNP on the results of IVW analysis, while the intercept of MR-Egger method and Cochrans Q test for horizontal multiplicity and heterogeneity were used to ensure the stability of the results, and funnel plots were used to analyze the potential biases of the study results. For the drug target CETP that reached COPD risk significance, co-localization analysis was used to test the exclusion restriction hypothesis. Results IVW analysis results indicated that increased genetic levels of LDL-C(OR=1.077, 95%CI: 1.001-1.159, P=0.046)and TC(OR=1.088, 95%CI: 1.002-1.181, P=0.044)were associated with an increased risk of COPD. Increased genetic levels of CETP were associated with an increased risk of COPD(OR=1.179, 95%CI: 1.052-1.321, P=0.004). MR-Egger regression, Cochrans Q test, and leave-one-out analysis suggested that the findings were reliable and robust. Conclusion Dyslipidemia is a causative factor in COPD. Increased levels of LDL-C and TC are associated with the pathogenesis of COPD. Among the three lipid-lowering drug targets, CETP is a promising candidate drug target for COPD.

Key words: Mendelian randomization, Statin drugs, Total cholesterol, Triglycerides, Low-density lipoprotein, High-density lipoprotein

中图分类号:

R563

吴彤,杨晶玉,林盪,徐婉茹,曾宇鋆. 基于孟德尔随机化方法探讨脂质和降脂药物与慢性阻塞性肺病的遗传关联[J]. 山东大学学报 (医学版), 2024, 62(5): 54-63.

WU Tong, YANG Jingyu, LIN Dang, XU Wanru, ZENG Yujun. Genetic association of lipids and lipid-lowering drugs with chronic obstructive pulmonary disease based on Mendelian randomization[J]. Journal of Shandong University (Health Sciences), 2024, 62(5): 54-63.

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