Association Between Rheumatoid Arthritis and Chronic Respiratory Diseases in A Japanese Population: A Mendelian Randomization Study

Objective Past observational studies have documented an association between Rheumatoid Arthritis (RA) and Chronic Respiratory Diseases (CRD). However, the establishment of a causal link remains elusive. Undertaking the approach of Mendelian Randomization (MR) analysis, this research aims to delve deeper into the probability of a causal connection between RA and CRD within the Japanese population. Methods Collated genome-wide association study (GWAS) data covering RA with 4,199 cases against 208,254 controls, asthma comprising 8,216 cases versus 201,592 controls, and Chronic Obstructive Pulmonary Disease (COPD) detailing 3,315 cases in contrast to 201,592 controls were derived from the repository of the Japanese Biobank. A selection of ten RA-related, eight asthma-related, and four COPD-related single nucleotide polymorphisms (SNPs) notable for their statistical significance (P < 5×10^−8) were identified as instrumental variables. The primary analytical technique employed to compute the odds ratios (ORs) and 95% confidence intervals (95%CIs) was the inverse variance-weighted (IVW) method, alongside the MR-Egger's protocol, weighted median, and weighted mode to reinforce the validity and solidity of the principal results. For scrutinizing possible implications of horizontal pleiotropy, we harnessed the MR-Egger’s intercept examination and the Mendelian Randomization Pleiotropy REsidual Sum and Outlier (MRPRESSO) test. Results Employing the inverse variance-weighted technique, we established a positive correlation between genetic predispositions for RA and actual occurrences of asthma (OR = 1.14; 95% CI: 1.04–1.24; P = 0.003). This correlation remained strong when testing the results utilizing various methods, including the MR-Egger's method (OR = 1.32; 95% CI: 1.09–1.60; P = 0.023), the weighted median (OR = 1.16; 95% CI: 1.06–1.26; P < 0.001), and the weighted mode (OR = 1.21; 95% CI: 1.11–1.32; P = 0.002). Furthermore, our findings from the inverse variance-weighted method also demonstrated a positive association between genetically predicted RA and COPD (OR = 1.12; 95% CI: 1.02–1.29; P = 0.021). However, no such link was discerned in supplementary analyses. In a shifted perspective - the reverse MR analysis - no correlation was identified between genetically predicted instances of asthma (IVW, P=0.717) or COPD (IVW, P=0.177) and RA. Conclusion Our study's findings confirm a causal correlation between genetically predicted RA and an elevated risk of either asthma or COPD. In contrast, our results offer no support to the presumed causal relationship between genetic susceptibility to either asthma or COPD and the subsequent development of RA. We underscore the necessity of additional MR studies, particularly when future GWAS present more comprehensive data for RA, asthma, and COPD within distinct East Asian or Japanese populations.