自身免疫性疾病与结核病的因果关系:一项两样本孟德尔随机化研究

Causal relationship between autoimmune diseases and tuberculosis:a two-sample Mendelian randomization study

目的:分析6种自身免疫性疾病[类风湿关节炎(RA)、系统性红斑狼疮(SLE)、强直性脊柱炎、1型糖尿病、炎症性肠病和银屑病]与结核病之间是否存在因果关系。方法:基于大样本全基因组关联研究汇总数据,采用逆方差加权法(IVW)、MR-Egger回归法和加权中位数法3种方法进行两样本孟德尔随机化分析,探究自身免疫性疾病与结核病之间因果关联。其中,以IVW为主要分析方法,其他2种方法作为进一步的验证,同时进行了水平多效性检验、异质性检验和留一法检验等敏感性分析检验结果可靠性。结果:IVW结果显示,RA和SLE与结核病存在正向的因果关系(ORRA=1.08,95%CIRA:1.01~1.14,PRA=0.023;ORSLE=1.06,95%CISLE:1.02~1.20,PSLE=0.002)。WME结果支持RA与结核病之间的因果关联(ORRA=1.12,95%CIRA:1.04~1.21,PRA=0.002;ORSLE=1.05,95%CISLE:0.99~1.10,PSLE=0.096)。而MR-Egger回归法结果无统计学意义(PRA=0.062,PSLE=0.205)。其他4种自身免疫性疾病并未发现与结核病存在因果关联(均P>0.05)。敏感性分析结果显示,所有结果均不存在多效性和异质性,留一法也提示所得结果稳健。结论:RA和SLE与结核病发生存在正向因果关系,RA和SLE患者结核病发生风险较高。

Objective To investigate the potential causal effects of six autoimmune diseases(rheumatoid arthritis[RA],systemic lupus erythematosus[SLE],ankylosing spondylitis,type 1 diabetes mellitus,inflammatory bowel disease and psoriasis)on tuberculosis.Methods Based on the large-sample genome-wide association studies summary data,a two-sample Mendelian randomization(MR)analysis via the inverse variance weighting(IVW),weighted median,and MR-Egger regression was applied.In this study,IVW was used as the main analytical method and the other two methods were used as further validation,while sensitivity analyses such as horizontal pleiotropy test,heterogeneity test and leave-one-out test were conducted to test the reliability of the results.Results RA and SLE presented a positive causal relationship with tuberculosis(OR RA=1.08,95%CI RA:1.01-1.14,P RA=0.023;OR SLE=1.06,95%CI SLE:1.02-1.20,P SLE=0.002).WME results supported a causal association between RA and tuberculosis(OR RA=1.12,95%CI RA:1.04-1.21,P RA=0.002;OR SLE=1.05,95%CI SLE:0.99-1.10,P SLE=0.096).However,the results of the MR-Egger method were not statistically significant(P RA=0.062,P SLE=0.205).The other four autoimmune diseases were not found to be causally associated with tuberculosis(all P>0.05).The results of the sensitivity analyses showed no pleiotropy or heterogeneity in all the results,and the leave-one-out method also suggested that the results obtained were robust.Conclusion There is a positive causal relationship between RA,SLE and tuberculosis,patients with RA and SLE are at increased risk of tuberculosis.