临床与病理杂志2025，Vol.45Issue(5)：539-550,12.DOI:10.11817/j.issn.2095-6959.2025.250143
PCSK9抑制剂和HMG-CoA还原酶抑制剂降低乳腺癌发生风险:代谢介导的孟德尔随机化证据
PCSK9 and HMG-CoA reductase inhibitors reduce breast cancer risk:Mendelian randomization evidence for metabolic mediation
摘要
Abstract
Objective:Dyslipidemia can increase oxidative stress and promote chronic inflammation,thereby contributing to tumorigenesis.Retrospective analyses have suggested that lipid-lowering drugs may have a modest protective effect on breast cancer,but evidence from large-scale prospective randomized controlled trials is lacking.This study aims to employ Mendelian randomization(MR)to investigate the causal relationships between lipid-lowering agents,proprotein convertase subtilisin/kexin type 9(PCSK9)and hydroxymethylglutaryl-CoA(HMG-CoA)reductase inhibitors,and breast cancer,and to evaluate the potential protective value of these drugs in reducing breast cancer risk. Methods:Genetic data related to exposures[low-density lipoprotein cholesterol(LDL-C)],outcomes(breast cancer),and mediators(circulating metabolites)were obtained from genome-wide association study(GWAS)databases.Single nucleotide polymorphisms(SNPs)were screened within±100 kilobase pairs of LDL-C as instrumental variables(IVs)for PCSK9 and HMG-CoA reductase inhibitors.Coronary heart disease(CHD)risk served as a positive control.The inverse-variance weighted(IVW)method served as the primary approach for causal effect estimation.Two-sample MR and two-step MR analyses were performed to assess causal associations between the 2 drugs and breast cancer risk,and to explore the mediating effects of circulating metabolites. Results:IVW analysis showed significant causal relationships for both PCSK9 inhibitors(OR=0.912,95%CI 0.845 to 0.979,P=0.007)and HMG-CoA reductase inhibitors(OR=0.827,95%CI 0.730 to 0.923,P<0.001)with reduced breast cancer risk.Two-step MR analyses indicated that the associations were partially mediated by specific metabolites.For PCSK9 inhibitors,the cholesterol to oleoyl-linoleoyl-glycerol(18꞉1 to 18꞉2)ratio and lignoceroyl sphingomyelin(d18꞉1/24꞉0)mediated 20.2%and 28.2%of the effect,respectively.For HMG-CoA reductase inhibitors,the adenosine 5'-monophosphate/glutamine ratio mediated 27.3%of the effect. Conclusion:PCSK9 and HMG-CoA reductase inhibitors are causally associated with a reduced risk of breast cancer,potentially exerting their protective effects through lipid metabolic reprogramming and energy metabolism regulation.Further mechanistic and clinical studies are needed to clarify the biological roles of circulating metabolites in this association.关键词
孟德尔随机化/前蛋白转化酶枯草溶菌素9/羟基甲基戊二酸酰辅酶A还原酶/乳腺癌/低密度脂蛋白胆固醇Key words
Mendelian randomization/proprotein convertase subtilisin/kexin type 9/hydroxymethylglutaryl-CoA reductase/breast cancer/low-density lipoprotein cholesterol引用本文复制引用
闵茜,董熠,刘书平,李清清..PCSK9抑制剂和HMG-CoA还原酶抑制剂降低乳腺癌发生风险:代谢介导的孟德尔随机化证据[J].临床与病理杂志,2025,45(5):539-550,12.基金项目
国家自然科学基金(82201488).This work was supported by the National Natural Science Foundation of China(82201488). （82201488）
