Genetically determined circulating levels ofcytokines and the risk of rheumatoid arthritis
Abstract Background: Accumulation of inflammatory leukocytes in articular tissues is the hallmark feature of rheumatoid arthritis (RA). Increasing evidence from observational studies have suggested that several cytokines are relevant in the disease process of RA. However, traditional observational studies are susceptible to bias from confounding and reverse causation; therefore, the potential causal association of individual cytokines with the risk of RA remains elusive. Our study aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of RA by conducting a two-sample Mendelian randomization (MR) study.Methods: We identified single nucleotide polymorphisms (SNPs) associated with circulating levels of cytokines and growth factors from a genome-wide association study (GWAS) including 8,293 participants of European ancestry as instrumental variables (IVs). The association estimates of these IVs with RA were obtained from a GWAS meta-analysis including 14,361 RA cases and 43,923 controls of European ancestry. MR analyses were performed using the random-effects inverse variance-weighted, weighted-median, MR-Egger and MR pleiotropy residual sum and outlier tests. Sensitivity analyses were further performed using restricted IVs excluding potential pleiotropic SNPs.Results: In the primary MR analysis, a total of 270 SNPs associated with circulating levels of 27 cytokines were identified and used as IVs. We found a suggestive inverse association between genetically determined circulating level of macrophage inflammatory protein-1β (MIP-1b) and the risk of RA [odds ratio (OR): 0.97, 95% confidence interval (CI) = 0.92-0.99, P = 0.016]. The association remained statistically significant in alternative MR analyses, and the causal effect estimate from sensitivity analysis using the restricted IVs was similar.Conclusions: Genetically determined elevated circulating level of MIP-1b was associated with a lower risk of RA. Further studies are warranted to determine how this MIP-1b and related pathways contribute to the development of RA.