Wu Dongze, Wong Priscilla, Lam Steven H M, Li Edmund K, Qin Ling, Tam Lai-Shan, Gu Jieruo
Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Medicine & Therapeutics, The Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
Rheumatology (Oxford). 2021 Apr 6;60(4):1963-1973. doi: 10.1093/rheumatology/keaa629.
To determine causal associations between genetically predicted TNF-α, IL-12p70 and IL-17 levels and risk of PsA.
The publicly available summary-level findings from genome-wide association studies (GWAS) was used to identify loci influencing normal physiological concentrations of TNF-α, IL-12p70 and IL-17 (n = 8293) among healthy individuals as exposure and a GWAS for PsA from the UK Biobank (PsA = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median and MR-Egger regression methods. Sensitivity analysis and MR-Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant.
Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α, IL-12p70 and IL-17 were identified as the instrumental variables. The IVW method indicated a causal association between increased IL-17 level and risk of PsA (β = -0.00186 per allele, s.e. = 0.00043, P = 0.002). Results were consistent in the weighted median method (β = -0.00145 per allele, s.e. = 0.00059, P = 0.014) although the MR-Egger method suggested a non-significant association (β = -0.00133 per allele, s.e. = 0.00087; P = 0.087). Single SNP MR results revealed that the C allele of rs117556572 was robustly associated with risk of PsA (β = 0.00210, s.e. = 0.00069, P = 0.002). However, no evidence for a causal effect was observed between TNF-α, IL-12p70, decreased IL-17 levels and risk of PsA.
Our findings provide preliminary evidence that genetic variants predisposing to higher physiological IL-17 level are associated with decreased risk of PsA.
确定基因预测的肿瘤坏死因子-α（TNF-α）、白细胞介素-12p70（IL-12p70）和白细胞介素-17（IL-17）水平与银屑病关节炎（PsA）风险之间的因果关联。
利用全基因组关联研究（GWAS）公开的汇总水平研究结果，确定影响健康个体中TNF-α、IL-12p70和IL-17正常生理浓度的基因座（n = 8293）作为暴露因素，并将来自英国生物银行的PsA全基因组关联研究（PsA = 900，对照 = 462033）作为结果。采用逆方差加权（IVW）、加权中位数和MR-Egger回归方法进行两样本孟德尔随机化（MR）分析。进行敏感性分析和MR-Egger回归分析以评估每个变异的异质性和多效性效应。
将GWAS中在全基因组水平上具有显著性的肿瘤坏死因子-α、白细胞介素-12p70和白细胞介素-17单核苷酸多态性（SNP）鉴定为工具变量。IVW方法表明IL-17水平升高与PsA风险之间存在因果关联（β = -0.00186/等位基因，标准误 = 0.00043，P = 0.002）。加权中位数方法的结果一致（β = -0.00145/等位基因，标准误 = 0.00059，P = 0.014），尽管MR-Egger方法显示无显著关联（β = -0.00133/等位基因，标准误 = 0.00087；P = 0.087）。单SNP MR结果显示，rs117556572的C等位基因与PsA风险密切相关（β = 0.00210，标准误 = 0.00069，P = 0.002）。然而，未观察到TNF-α、IL-12p70、IL-17水平降低与PsA风险之间存在因果效应的证据。
我们的研究结果提供了初步证据，表明倾向于导致更高生理IL-17水平的基因变异与PsA风险降低相关。
