使用孟德尔随机化(MR)设计评估白细胞介素(ILs)与类风湿关节炎(RA)之间的因果关系。
从三个全基因组关联元分析中获得了10个IL的遗传仪器和汇总水平数据。RA的相应数据来自22个全基因组关联研究(14,361例和43,923例对照)和FinnGen联盟(6236例,4596例血清阳性,1937年血清阴性病例,和172,834个控件)。进行正向和反向MR分析。
RA的比值比(OR)为2.08(95%置信区间(CI),1.56-2.77;p<0.001),2.14(95%CI,1.85-2.49;p<0.001),遗传预测的IL-1β增加一个标准偏差为0.95(95%CI,0.92-0.97;p<0.001),IL-6和IL-6受体拮抗剂(IL-6ra)水平,分别。基因预测的IL-1受体拮抗剂(IL-1ra)(OR,0.85,95%CI,0.76,0.96;p=0.010)和IL-18(OR,1.07,95%CI,1.00,1.15;p=0.043)水平与RA风险有关。观察到血清阳性RA的亚型特异性关联(IL-1β,IL-1ra,和IL-6)和血清阴性RA(IL-2受体α亚基,IL-8和IL-18)。反向MR分析发现RA的遗传倾向与IL-6受体拮抗剂之间存在暗示性关联(变化0.015;95%CI,0.003-0.028;p=0.015)。
这项MR研究表明,长期抑制IL-1和IL-6可能会降低RA的风险,尤其是血清阳性RA。参与IL-6信号通路的IL的上调似乎是RA的下游效应,这支持阻断IL-6治疗RA。
To assess the causality of the associations between interleukins (ILs) and rheumatoid arthritis (RA) using Mendelian randomization (MR) design.
Genetic instruments and summary-level data for ten ILs were obtained from three genome-wide association meta-analyses. Corresponding data on RA were obtained from a meta-analysis of 22 genome-wide association studies (14,361 cases and 43,923 controls) and the FinnGen consortium (6236 cases, 4596
seropositive cases, 1937 seronegative cases, and 172,834 controls). Forward and reverse MR analyses were performed.
The odds ratios (ORs) of RA were 2.08 (95% confidence interval (CI), 1.56-2.77; p<0.001), 2.14 (95% CI, 1.85-2.49; p<0.001), and 0.95 (95% CI, 0.92-0.97; p<0.001) for one standard deviation increase in genetically predicted IL-1β, IL-6 and IL-6 receptor antagonist (IL-6ra) levels, respectively. There were suggestive associations of genetically predicted IL-1 receptor antagonist (IL-1ra) (OR, 0.85, 95% CI, 0.76, 0.96; p=0.010) and IL-18 (OR, 1.07, 95% CI, 1.00, 1.15; p=0.043) levels with RA risk. Subtype-specific associations were observed for
seropositive RA (IL-1β, IL-1ra, and IL-6) and seronegative RA (IL-2 receptor alpha subunit, IL-8, and IL-18). Reverse MR analysis found a suggestive association between genetic liability to RA and IL-6 receptor antagonist (change 0.015; 95% CI, 0.003-0.028; p=0.015).
This MR study suggests that long-term IL-1 and IL-6 inhibition may reduce the risk of RA, particularly
seropositive RA. Upregulations of ILs involved in IL-6 signaling pathways appears to be downstream effects of RA, which supports the blocking IL-6 treatment for RA.