Genetic association of lipids and lipid-lowering drugs with chronic obstructive pulmonary disease based on Mendelian randomization
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 Mende-lian 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 data-base(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 tar-gets 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 candi-date drug target for COPD.
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