This MR study was conducted to explore the potential causal connection between RA and chronic respiratory diseases in The Japanese Population. The data suggest a positive correlation between the genetic likelihood of RA and an elevated risk of asthma within the Japanese demographic. These conclusions are coherent across alternative MR techniques such as MR-Egger, Weighted Median, and Weighted Mode. A similar positive linkage was discerned between genetic predispositions to RA and an increased probability of developing COPD in the same population. Nonetheless, this relationship did not reach statistical significance when assessed via other MR method (MR-Egger, Weighted Median, and Weighted Mode). Conversely, in reverse MR analyses, no causative association was identified between asthma or COPD and the susceptibility to RA.
Earlier epidemiological inquiries have identified a comparatively higher incidence of asthma within individuals diagnosed with RA as opposed to the general population. Kim et al.[10] utilized data sourced from the Health Insurance Review and Assessment Service - National Sample Cohort (HIRA-NSC) in Korea, spanning the period of 2002 to 2013. This dataset comprised adult participants aged over twenty, with a sample of 6,695 RA patients and 26,780 control subjects, to appraise the historical occurrence of asthma. Results from this cohort highlighted a more prominent hazard ratio for asthma presence in the RA group in contrast to the control group (HR = 1.23, 95%CI=1.15-1.32). A parallel cohort study conducted in Taiwan deduced a similar pattern[11], documenting that the incidence rate of asthma within the RA cohort was more than double the rate observed in the non-RA cohort (HR = 2.07). In 2013, Nannini et al. were pioneers in reporting that individuals afflicted with RA also showed a heightened prevalence of COPD when measured against the general populace (HR: 1.54, 95% CI 1.01-2.34)[27]. Subsequent research efforts have reinforced this linkage[7, 28-30], with a meta-analysis assimilating data from eight studies presenting a marked elevation in COPD risk for RA patients compared to controls (RR=1.82, 95%CI=1.55-2.10). These findings are in synergy with our own results regarding the causal impact of RA on asthma or COPD[31].
Though it was once widely accepted that RA was primarily associated with Th1 lymphocyte-induced inflammation, and asthma largely influenced by Th2 lymphocytes, the connection between diseases driven by these cell types was not clearly understood. This led to a prevailing notion that RA and asthma may co-occur in patients without sharing a direct biological relationship. Contrasting this older view, more recent studies have unveiled a prominent involvement of Th1 lymphocytes in the pathogenesis of asthma, particularly severe asthma[32]. GWAS conducted by Li et al. have discovered that cumulative genetic scores of SNPs within the genes IL12A, IL12RB1, STAT4, and IRF2, all part of the Th1 pathway, bear a negative association with forecasted FEV1 percentages and a positive one with the gravity of asthma symptoms[33]. Adding to this, Raundhal et al. undertook an examination of bronchoalveolar lavage cells from asthma patients ranging from mild to severe and discerned an intensified IFN-γ (Th1) immune response in those with severe asthma, alongside subdued Th2 and IL-17 responses[34].
Th17 cells are recognized as fundamental players in the pathogenesis of RA [35]. Evidence from asthma models in mice has demonstrated that IL-17A and IL-17F, cytokines produced by Th17 cells, are instrumental in prompting the proliferation and mobilization of mast cells, which are pivotally involved in orchestrating airway inflammation[36, 37]. These cytokines also exacerbate TH2-associated eosinophilia[38], and contribute to an enhanced state of airway hyperresponsiveness and Mucin5AC secretion[39]. Observational studies have reported augmented levels of IL-17 in the respiratory tracts of individuals with asthma[40], proposing a conceivable link underlying the co-prevalence of RA and asthma. Moreover, anti-citrullinated protein antibodies(ACPAs), known to be intimately linked to the onset of RA[41, 42], have also been correlated with pulmonary interstitial pathologies[43]. Research by Alessandra et al. uncovered an associative trend between heightened amounts of ACPAs and an incremented occurrence of asthma and COPD within female patients suffering from RA[44]. These findings raise the possibility that RA could trigger the genesis of asthma and COPD via mechanisms driven by ACPA-related inflammation, a process that may even precede the clinical manifestation of joint symptoms[44].
Presently, a prevailing hypothesis in the medical community posits that autoimmune and inflammatory reactions are central to the onset of COPD in patients with RA[30, 45, 46]. This is chiefly characterized by a heightened production of autoantibodies that target a wide array of the body's own proteins, alongside elevated levels of pro-inflammatory markers in the circulatory system of those afflicted with COPD[47, 48]. It is theorized that the inflammatory processes associated with RA may adversely impact the cells lining the alveoli in the lungs, which could lead to alveolar wall degradation and as a consequence, COPD[49].
To our knowledge, there have been four MR studies based on European populations assessing the potential causal relationship between RA and asthma or COPD [16-19] The conclusions from Cao et al. [19] are similar to ours, showing a positive association between genetically predicted RA and risk of COPD or asthma, however, they didn't conduct reverse MR studies. The conclusions from Yu et al. [16] also showed a positive association between genetically predicted RA and COPD risk, but no association was found for COPD as a genetic predictor of RA risk. The findings of Chen et al.[17] and Yan et al.[18] indicated a positive association between genetically predicted asthma and RA risk, but their reverse MR studies didn't suggest a correlation between them.
Genome and disease characteristics differences may partly explain the differences between previous studies and our research. We have compared our SNPs with those in the four European MR studies, and only one SNP in one of the studies overlapped with ours, none of the SNPs from the remaining studies overlapped with our research. This suggests that effective genetic variation may differ among different races. Moreover, considering that the underlying mechanisms may differ between mild to moderate asthma and severe asthma[32], but most GWAS data did not specifically categorize asthma subtypes, this has also led to differences in MR analysis results.
Our MR study, which probed into the putative causative link between RA and obstructive pulmonary disorders such as asthma and COPD within The Japanese Population, encountered several constraints. Initially, the exclusive utilization of GWAS data from Japanese groups suggests that the inferences we reached may not be applicable to other ethnic demographics. Another concern pertains to the potential for bias––specifically, the winner's curse and weak instrument bias [26, 50] —stemming from the use of SNPs for both exposure and outcome derived from an identical sample set, possibly leading to an overestimation in the MR analytical results. Nonetheless, an existing empirical investigation has demonstrated that such biases are unlikely to exert a significant distortion on the findings[26]. By incorporating a stringent GWAS significance cut-off in our sensitivity analysis, we ascertained that there was no discernible association between genetically forecasted RA and the likelihood of developing asthma or COPD. Further MR studies underscored by more granular and expansive GWAS data within East Asian and The Japanese Population are requisite for more conclusive results.