| Objectives:The results of studies on the causal relationship between antioxidants and breast cancer are currently inconsistent.Therefore,this article conducted a two-sample Mendelian randomization analysis based on genome-wide association studies to investigate whether antioxidants may have a potential causal relationship with breast cancer and its subtypes.Methods:This study used enzymatic antioxidants（glutathione S-transferase,catalase,superoxide dismutase,glutathione peroxidase）as well as non-enzymatic antioxidants（albumin,retinol,total bilirubin,uric acid,vitamin E,vitamin C）as exposure factors;breast cancer,estrogen receptor-negative breast cancer,and estrogen receptor-positive breast cancer as outcome factors,and explored the causal associations using two-sample Mendelian randomization analysis.Instrumental variables that were significantly associated with exposure factors(P<5×10-5)were first selected separately from the exposure factor（antioxidants）dataset.Afterwards,instrumental variables with linkage disequilibrium（r2>0.001and genetic distance<1000）and F-statistic values<10 were excluded.The data information corresponding to the remaining instrumental variables was then extracted from the outcome factors（breast cancer and subtype）separately.Two-sample Mendelian randomization analysis and graphing were performed in R software,and data were analyzed using inverse variance weighting,Egger regression Mendelian randomization,and weighted median methods.Quality control included heterogeneity analysis,multiple validity test,and sensitivity analysis.Heterogeneity analysis was performed by Cochran’s Q test,multiplicity test by Egger regression Mendelian randomization method,and sensitivity analysis by leave-one-out method and funnel plot method.A significant causal relationship between exposure factors and outcome was considered when P<8.33×10-4 by Bonferroni correction,and a suggestive association between exposure factors and outcome factors was considered when P was between8.33×10-4 and 0.05.Results:（1）There was no causal relationship between enzyme antioxidants and breast cancer and subtypes（P>0.05）.（2）There was no causal relationship between non-enzymatic antioxidants other than total bilirubin and breast cancer and subtypes（P>0.05）.（3）There was a potential causal effect between total bilirubin and overall risk of breast cancer（OR,1.016;95%CI,1.002-1.029;P=0.026）.There was also a potential causal effect between total bilirubin and risk of estrogen receptor-positive breast cancer（OR,1.016;95%CI,1.001-1.031;P=0.041）,but not between total bilirubin and risk of estrogen receptor-negative breast cancer（OR,1.013;95%CI,0.991-1.036;P=0.247）.Conclusions:By Mendelian randomization analysis,the results suggested a potential causal effect between total bilirubin and the risk of breast cancer and estrogen receptor-positive breast cancer.There was no causal effect between non-enzymatic antioxidants other than total bilirubin and enzymatic antioxidants and the risk of breast cancer and subtypes. |
