基于孟德尔随机化分析多种代谢指标与乳腺癌发生的潜在因果关系OA

Objective To explore the potential causal relationship between multiple metabolic parameters and the risk of breast cancer using Mendelian randomization(MR)method.Methods A total of 13 metabolic parameters were enrolled as exposure factors in this study.The genetic instrumental variables for these factors were derived from the corresponding Genome-Wide Association Study(GWAS)databases,and the outcome data for breast cancer were obtained from the FinnGen database.Single nucleotide polymor-phisms(SNPs)that conformed to the three core assumptions of MR were screened as instrumental variables.The inverse variance weighted(IVW)method was adopted as the primary analytical approach,and MR-Egger regression,the weighted median(WM)method,the weighted mode method and the simple mode method were combined to comprehensively evaluate the causal relationships between exposures and outcome.Pleiotropy test,heterogeneity test and leave-one-out sensitivity analysis were performed to ensure the reliability of MR results.Results Among the 13 exposure factors,apolipoprotein A-V(apoA-V),the ratio of triglycerides to total lipids in low-density lipoprotein(TG/LDL total lipid),hypertension,diastolic blood pressure(DBP),body mass index(BMI),and waist-hip ratio adjusted for BMI(WHRadjBMI)were identified as protective factors for breast cancer.Proinsulin and insulin receptor(INSR)were confirmed as risk factors for breast cancer.No causal relationship with statistical significance was found between breast cancer and the remaining parameters,including triglycerides(TG),apoB,total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C).The results of sensitivity analyses showed that there was no significant horizontal pleiotropy or heterogeneity in the selected instrumental variables,and the MR effect estimates were not affected by any indi-vidual SNP.Conclusion Proinsulin and insulin receptor are associated with an elevated risk of breast cancer,while apoA-V,TG/LDL total lipid,HTN,DBP,BMI and WHRadjBMI are correlated with a reduced risk of breast cancer.These findings indicate that there are differential associations between various metabolic parameters in human body and the risk of breast cancer.