Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Orthopedic Research Institute of Zhejiang University, Hangzhou, China.
Front Immunol. 2021 Sep 3;12:707617. doi: 10.3389/fimmu.2021.707617. eCollection 2021.
To find out the genetic association between IL6 and autoimmune arthritis.
We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets. Furthermore, a sex-stratified MR study was performed to identify sexual dimorphism in the association between IL6 and autoimmune arthritis. Then, LocusZoom plots were displayed based on the IL6R gene region to present evidence of genetic colocalization between diseases.
The MR result denoted a genetic association between the increased level of IL-6 signaling and risk of RA (β=0.325, 95%CI 0.088, 0.561, p=7.08E-03) and AS (β=1.240, 95%CI 0.495, 1.980, p=1.1E-03). Accordingly, sIL6R was found to have negatively correlation with the onset of RA (β=-0.020, 95%CI -0.0320, -0.008, p=1.18E-03) and AS (β=-0.125, 95%CI -0.177, -0.073, p=2.29E-06). However, no genetic association between IL6/sIL6R and PsA was detected. The gender-stratified MR analysis showed that IL6 was associated with AS in the male population, with RA in the female population, and with PsA in the male population. Additionally, ADAR, a gene identified by a sensitive test, could be the reason for the nonsignificant association between IL6 and PsA in a pooled population.
Our findings showed that the overactive IL6 signal pathway led to autoimmune arthritis, especially in RA and AS. Sexual difference was also observed in IL6-intermediate susceptibility to autoimmune arthritis.
探究白细胞介素 6（IL6）与自身免疫性关节炎之间的遗传关联。
我们采用多组全基因组关联研究（GWAS）数据集进行了两样本孟德尔随机化（MR）研究。此外，还进行了一项性别分层 MR 研究，以确定 IL6 与自身免疫性关节炎之间关联的性别二态性。然后，根据 IL6R 基因区域显示定位图谱，以呈现疾病之间遗传共定位的证据。
MR 结果表明，IL-6 信号通路水平升高与类风湿关节炎（RA）（β=0.325，95%CI 0.088，0.561，p=7.08E-03）和强直性脊柱炎（AS）（β=1.240，95%CI 0.495，1.980，p=1.1E-03）风险之间存在遗传关联。因此，可溶性白细胞介素 6 受体（sIL6R）与 RA（β=-0.020，95%CI -0.0320，-0.008，p=1.18E-03）和 AS（β=-0.125，95%CI -0.177，-0.073，p=2.29E-06）的发病呈负相关。然而，未检测到 IL6/sIL6R 与银屑病关节炎（PsA）之间存在遗传关联。性别分层 MR 分析表明，IL6 与男性人群中的 AS、女性人群中的 RA 和男性人群中的 PsA 相关。此外，ADAR，一种通过敏感测试鉴定的基因，可能是 IL6 与银屑病关节炎在混合人群中无显著关联的原因。
我们的研究结果表明，过度活跃的 IL6 信号通路导致自身免疫性关节炎，尤其是类风湿关节炎和强直性脊柱炎。在 IL6 对自身免疫性关节炎的中间易感性方面也观察到了性别差异。
