Zhu Jingjing, Niu Zheng, Alfredsson Lars, Klareskog Lars, Padyukov Leonid, Jiang Xia
The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
Department of Gynecology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Arthritis Res Ther. 2021 Apr 9;23(1):108. doi: 10.1186/s13075-021-02495-x.
Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA.
We collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (N = 14,361, N = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions.
We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (OR = 1.06 [0.98-1.15]; OR = 1.05 [0.98-1.11], OR = 0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (OR = 1.06 [0.97-1.15], OR = 1.05 [0.98-1.13], OR = 0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (OR = 1.03 [0.94-1.12], OR = 1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis.
Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.
激素生殖因素被认为在类风湿关节炎（RA）的病因中起重要作用，RA是一种主要影响女性的自身免疫性炎症性疾病。我们进行了一项两样本孟德尔随机化（MR）研究，考察初潮年龄（AAM）、自然绝经年龄（ANM）和首次生育年龄（AFB）这三种相关暴露因素与RA风险之间的关系。
我们收集了迄今为止在AAM（N = 329,345）、ANM（N = 69,360）、AFB（N = 251,151）以及RA（N = 14,361，N = 43,923）研究中进行的最大规模全基因组关联研究（GWAS）的汇总统计数据，所有研究对象均为欧洲血统。我们使用数百个与暴露相关的基因变异构建了强工具变量，并通过不同的MR方法估计因果关系，包括逆方差加权法、MR-Egger回归法和加权中位数法。我们进行了多变量MR以控制特别是通过肥胖和社会经济地位起作用的多效性效应。我们还进行了重要的敏感性分析以验证模型假设。
我们没有发现任何证据支持基因预测的生殖因素与RA风险之间存在因果关联（比值比[OR]=1.06[0.98 - 1.15]；OR = 1.05[0.98 - 1.11]，OR = 0.85[0.65 - 1.10]）。去除回文单核苷酸多态性（SNPs）后结果仍然一致（OR = 1.06[0.97 - 1.15]，OR = 1.05[0.98 - 1.13]，OR = 0.81[0.61 - 1.07]），或者排除与潜在混杂特征相关的SNPs后结果也一致（OR = 1.03[0.94 - 1.12]，OR = 1.04[0.95 - 1.14]）。通过逐一剔除分析未发现异常的工具变量。
我们的MR研究没有令人信服地支持以初潮年龄、绝经年龄和首次生育年龄为代表的生殖因素对RA发病有因果效应。尽管我们使用的工具变量集大幅增加，但这些工具变量仅解释了暴露因素表型变异的一小部分。我们关于这个主题的知识仍然不足，未来应设计更大样本量的研究来重复或反驳我们的发现。
