Adipokines and risk of rheumatoid arthritis: a Mendelian randomization study

Background: Circulating adipokines levels have been reported to be associated with the risk of rheumatoid arthritis (RA). However, it is still unclear whether these associations are causal or biased by reverse causation or residual confounding. This study aimed to assess potential causal roles of five adipokines (namely, adiponectin, leptin, resistin, chemerin, and retinol-blinding protein 4 [RBP4]) in the occurrence of RA. Methods: : We conducted a two-sample Mendelian randomization analysis to investigate these associations. We used summary-level data from genome-wide association studies (GWASs) for adipokines in individuals of European ancestry as the exposure, and a separate large-scale meta-analysis of a GWAS which included 14,361 RA cases and 43,923 controls of European ancestry as the outcome. Genetic variants were selected as instrumental variables if robustly genome-wide significant in their associations with adipokines. The causal effects were estimated using the inverse-variance weighted method in the primary analysis. Sensitivity analyses were performed to warrant that bias due to genetic pleiotropy was unlikely. Results: : The circulating resistin was found to be the only adipokinetic factor having statistical significance, with higher levels causally associated with the risk of RA (odds ratio: 1.28; 95% confidence interval: [1.07, 1.53] per unit increase in the natural log-transformed resistin). In contrast, associations of adiponectin, leptin, chemerin, and RBP4 with risk of RA were not statistically significant. The MR assumptions did not seem to be violated. Sensitivity analyses yielded consistent findings. Conclusions: : Genetically predicted circulating resistin levels were positively associated with RA risk. Our analysis suggested that resistin may play a notable causal role in RA pathogenesis. It would be beneficial for the development of clinical as well as public health strategies that target appropriate levels of resistin for future RA intervention.