In this study, we used two-sample MR to investigate whether RA is causally associated with pneumonia and its subtypes in a European population. The summary statistical data that we used came from publicly published studies. The present MR analysis showed that RA was associated with an increased risk of pneumonia, but it did not cause death or a need for critical care.
RA is neither a metabolic disease, such as diabetes and hyperuricaemia, nor a disease of measurable severity, such as hypertension; rather, its pathogenesis is complex, and there are associated complications 23. The relationship of RA with pneumonia has also been a research focus 24. Pulmonary disease represents an important extra-articular manifestation of RA 25. The mechanisms of pneumonia in RA are poorly understood, but genetic and environmental factors are considered to play a role.
Previous studies indicated associations between RA and pneumonia. A large-scale cohort study found that RA is associated with a significantly greater risk of interstitial lung disease (ILD) 24,26. There have also been observational studies linking RA with obstructive pneumonia 25,27. Various studies have shown a link between RA and lung disease 28. However, there are few reports on the relationship between RA and pneumonia. At present, it is not clear whether there is a causal relationship between RA and pneumonia.
In our analysis, RA was a risk factor for pneumonia, but it did not cause death or a need for critical care. Some have suggested two potential pathways from RA to lung disease 29. In one of these pathways, RA-associated lung disease begins in synovial tissue, followed by an immune response against citrullinated proteins, which then cross-react with similar antigens in the lungs. This hypothesis is justified by the observation that most patients with rare lung disease will develop joint disease before lung involvement. In the second pathogenic paradigm, immune tolerance breaks down in the lungs, and ILD (including UIP) triggers an immune response to citrulline proteins that rediffuse to the joints. This hypothesis has been proven by observation experiments 30,31. Our study can provide support for the above two pathway hypotheses from the perspective of the genome.
Our study is the first to use two-sample MR analysis to find that RA can cause pneumonia, which proves the causal relationship between the two from a genetic point of view. In addition, in the MR analysis, we used the traditional IVW, weighted median, MR-PRESSO and MR–Egger methods to prevent a misestimation of causality. Finally, the results of horizontal pleiotropy analysis and heterogeneity analysis showed that the use of these genetic tools does not lead to horizontal multiplicity or heterogeneity, and the results of the leave-one-out test showed that our results are robust.
There are limitations to our study. First, although many RA cases were found in the current GWAS analysis, they could not be stratified or adjusted for analysis. In addition, MR analysis reflected lifetime exposure to changes in RA during pneumonia; however, it was not possible to determine how a specific time exposure affected the results. It is undeniable that the sample size of the GWAS analysis was large, but increasing the sample size could indeed improve the accuracy of the results.