基于孟德尔随机化法的自身免疫性疾病与乳腺癌发病风险相关性探讨

Correlation between autoimmune diseases and breast cancer risk based on Mendelian randomization method

目的:利用孟德尔随机化法进行分析,探究各类自身免疫性疾病(克罗恩病、银屑性关节病、系统性红斑狼疮、骶髂炎)与乳腺癌发病风险间的因果关联,并以克罗恩病为例探究中介因素,寻找疾病促进乳腺癌发展的原因。方法:在全基因组关联研究的汇总数据中提取工具变量,选取自身免疫性疾病作为暴露因素,乳腺癌作为结局因素,筛选出与暴露因素明确相关的单核苷酸多态性位点作为工具变量,采用Egger-intercept法检验水平多效性,留一法进行敏感性分析,通过逆方差加权分析法评估暴露与结局间的因果关系。结果:逆方差加权法分析结果显示克罗恩病(OR=1.001,95%CI:1.000~1.002)、银屑性关节病(OR=1.002,95%CI:1.001~1.005)、骶髂炎(OR=1.001,95%CI:1.000~1.002)是乳腺癌的危险性因素,系统性红斑狼疮(OR=0.999,95%CI:0.998~1.000)是乳腺癌的保护性因素,克罗恩病与乳腺癌的因果关联中CD39^(+)CD4^(+)调节性T细胞是主要中介因子,中介占比为6%。C反应蛋白、P-选择素糖蛋白配体1、IL-17B受体等炎性因子均为乳腺癌的危险性因素。结论:炎症会加剧乳腺癌疾病进展,提示炎症生物标志物可能用于监测疾病进展及开发预防或治疗乳腺癌新的抗炎药物。

Objective:We used Mendelian randomization method for analysis in this study to explore the causal associations between various autoimmune diseases(Crohn's disease,psoriatic arthropathy,systemic lupus erythematosus,sacroiliitis)and the risk of breast cancer development.Methods:Tool variables were extracted from pooled data of genome-wide association studies.Autoimmune diseases were selected as exposure factors,while breast cancer was considered as the outcome factor.Single nucleotide polymorphisms(SNPs)that were clearly associated with the exposure factors were chosen as tool variables.The Egger-intercept method was employed to test for level heterogeneity,and sensitivity analysis was conducted using leave-one-out method.The inverse variance weighted method was utilized to evaluate the causal relationship between exposure and outcome.Results:The results from inverse variance weighted analysis indicated that Crohn's disease(OR=1.001,95%CI:1.000~1.002),psoriatic arthritis(OR=1.002,95%CI:1.001~1.005),and sacroiliitis(OR=1.001,95%CI:1.000~1.002)were identified as risk factors for breast cancer,whereas systemic lupus erythematosus(OR=0.999,95%CI:0.998~1.000)exhibited a protective effect against breast cancer development.CD39^(+)activated CD4^(+)regulatory T cells emerged as a primary mediating factor in establishing a causal link between Crohn's disease and breast cancer,accounting for 6%of the total mediation effect.Additionally,inflammatory markers such as C-reactive protein,P-selectin glycoprotein ligand 1,and IL-17B receptor were all found to be associated with an increased risk of developing breast cancer.Conclusion:Inflammation exacerbates the progression of breast cancer,thus suggesting that inflammation biomarkers may serve as valuable tools for monitoring disease progression and developing novel anti-inflammatory drugs aimed at preventing or treating breast cancer.