Causal relationship between rheumatoid arthritis and thyroid dysfunction: A two-sample Mendelian randomization study

Background Growing evidence has shown that Rheumatoid arthritis (RA) is associated with hyperthyroidism and hypothyroidism.However, the reciprocal cause-and-effect relationship among those three factors has not yet been substantiated. Methods We conducted a two-sample Mendelian randomization (TSMR) study with bidirectional analysis. We selected specific single nucleotide polymorphisms (SNPs) associated with rheumatoid arthritis (RA), hyperthyroidism, and hypothyroidism as instrumental variables. Every single nucleotide polymorphism (SNP) was derived from a genome-wide association study conducted specifically on individuals of European ancestry. For this study, the primary approach utilized to estimate the reciprocal causal relationship between rheumatoid arthritis (RA) and hyperthyroidism or hypothyroidism was the inverse-variance weighting (IVW) method. Finally, the robustness of the results was tested using sensitivity analysis and pleiotropic test. Results The utilization of the IVW method to detect rheumatoid arthritis (RA) revealed an elevated relative risk of hyperthyroidism (OR=1.33, 95% CI=1.17-1.52, P=2.407e-05), as well as a heightened risk of hypothyroidism (OR=1.29, 95% CI: 1.21-1.37, P=3.614e-16). On the flip side, it was observed that hypothyroidism might also elevate the relative risk of developing rheumatoid arthritis (OR=1.57, 95% CI=1.30-1.91, P=4.211e-06). Nevertheless, the analysis using the inverse-variance weighting (IVW) method suggested that there might not be a causal relationship between hyperthyroidism and rheumatoid arthritis (IVW: P=0.769). Finally, a sensitivity analysis was performed to assess the reliability of the results, and it indicated that no pleiotropic effects were observed, further bolstering the validity of the findings. Conclusion The findings of this study demonstrate a bidirectional causal relationship between genetic susceptibility to rheumatoid arthritis (RA) and an augmented risk of developing hypothyroidism, and vice versa. Moreover, this research establishes a positive causal relationship between genetic susceptibility to rheumatoid arthritis (RA) and an elevated risk of hyperthyroidism. However, it does not provide evidence to support a causal relationship between genetic susceptibility to hyperthyroidism and the development of RA.