DataSheet1_Primary ovarian insufficiency consequence of autoimmune diseases: a bidirectional two-sample Mendelian randomization study.pdf

BackgroundObservational studies suggest the risk of primary ovarian insufficiency (POI) is increased in autoimmune disorders (AIDs), but it is unclear whether there is a causal relationship. Therefore, we aimed to investigate the bidirectional causality between 20 AIDs and POI using Mendelian randomization (MR) analysis.
MethodsA bidirectional two-sample MR investigation was designed by using publicly accessible summary-level data from genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by several sensitivity analyses. Cochran Q test was used to evaluate SNP estimate heterogeneity. MR-Egger and MR-PRESSO methods were utilized to detect horizontal pleiotropy.
ResultsThe MR analyses revealed that genetically determined coeliac disease (CeD) (OR = 1.124, 95% CI 1.033-1.224, P = 0.007), vitiligo (OR = 1.092, 95% CI 1.003-1.188; P = 0.042), systemic lupus erythematosus (SLE) (OR = 1.122, 95% CI 1.030-1.223, P = 0.008), and selective immunoglobulin A deficiency (SIgAD) (OR = 0.866, 95% CI: 0.776-0.967, P = 0.011) exhibited significant causal relationships with POI. We also found suggestive evidence of positive effect of Addison’s disease (AD) towards POI (OR5e-6 = 1.076, 95% CI 1.002-1.154, P = 0.043).
ConclusionThis comprehensive MR analysis indicated that SLE, CeD, vitiligo, and AD caused an increased risk of POI, SIgAD was associated with a decreased risk of POI. These insights carry profound clinical implications, particularly emphasizing the early intervention for women with AIDs/POI who wish to preserve their reproductive potential or plan for future pregnancies.

背景 观察性研究提示，自身免疫性疾病（autoimmune disorders, AIDs）患者的原发性卵巢功能不全（primary ovarian insufficiency, POI）发病风险升高，但二者是否存在因果关联尚不明确。为此，本研究旨在利用孟德尔随机化（Mendelian randomization, MR）分析探究20种自身免疫性疾病与POI之间的双向因果关系。
方法 本研究设计了双向两样本MR分析，采用公开可获取的全基因组关联研究（genome-wide association studies, GWAS）汇总级数据。以逆方差加权（inverse variance weighted, IVW）法作为主要分析手段，并辅以多项敏感性分析。使用Cochran Q检验评估单核苷酸多态性（SNP）效应量的异质性，采用MR-Egger与MR-PRESSO方法检测横向多效性。
结果 MR分析显示，遗传因素决定的乳糜泻（coeliac disease, CeD）（比值比[OR]=1.124，95%置信区间[CI]=1.033~1.224，P=0.007）、白癜风（OR=1.092，95%CI=1.003~1.188；P=0.042）、系统性红斑狼疮（systemic lupus erythematosus, SLE）（OR=1.122，95%CI=1.030~1.223，P=0.008）以及选择性IgA缺乏症（selective immunoglobulin A deficiency, SIgAD）（OR=0.866，95%CI=0.776~0.967，P=0.011）与POI存在显著因果关联。本研究还观察到，艾迪生病（Addison’s disease, AD）对POI存在潜在的正向效应（OR=1.076，95%CI=1.002~1.154，P=0.043）。
结论 本项全面的MR分析表明，SLE、CeD、白癜风及AD可升高POI的发病风险，而SIgAD则与POI发病风险降低相关。上述研究结果具有重要的临床意义，尤其提醒临床需对希望保留生育能力或计划妊娠的自身免疫性疾病/POI女性患者尽早开展干预。