The Causal Relationship Between Rheumatoid Arthritis and Pneumonia: A Mendelian Randomization Study

Abstract

Background

At present, it is not clear whether there is a causal relationship between rheumatoid arthritis (RA) and pneumonia.

Method

Single-nucleotide polymorphisms (SNPs), obtained from a genome-wide association study (GWAS) of RA, were used as instrumental variables. Inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode and weighted mode methods were used to investigate causal effects. We applied MR-PRESSO methods and MR–Egger methods to investigate sensitivity. The heterogeneity of individual genetic variants was evaluated by Cochran's Q test and a leave-one-out analysis.

Results

Forty-two SNPs were selected as instrumental variables. The results of the IVW method were very significant (OR, 1.056 for pneumonia per log-odds increment in RA risk, 95% CI 1.034–1.077; p = 1.87E-07), and other methods were also statistically significant. The results of the IVW method showed a causal effect of genetically determined RA on pneumonia (critical care) (OR, 1.053, 95% CI 1.001–1.106; p = 0.044) but no causal effect of genetically determined RA on pneumonia (death) or pneumonia (28-day death in critical care)

Conclusions

The study showed that RA was associated with an increased risk of pneumonia, but it did not cause death or a need for critical care.

1. Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with autoimmune characteristics that is often accompanied by synovitis as well as cartilage and bone damage¹. If not treated properly, RA may lead to cumulative joint damage and irreversible disability ^2,3. The prevalence of RA in Caucasians is in the range of 0.5–1.0%, which has been verified in most epidemiological studies in Western countries ^4,5. RA has a strong genetic component in populations and strong heritability ⁶. Pneumonia has been found to be associated with RA in many observational studies and is a complication of RA ⁷.

Pneumonia is a common disease that seriously affects human health. Pneumonia is an acute respiratory infection that affects the alveoli and distal bronchi ⁸. Data from the Global Burden of Diseases (GBD) study showed that lower respiratory infections, including pneumonia and bronchiolitis, affected 489 million people in 2009⁹. The identification of more therapeutic factors is of great significance for the early prevention and treatment of pneumonia as a complication of RA¹⁰. Mette et al. suggested that high RA disease activity before admission may increase the mortality of pneumonia¹¹. However, the causal relationship between RA and pneumonia is unclear. Therefore, we used Mendelian randomization (MR) to investigate the causal relationship between RA and pneumonia and its subtypes¹².

Mendelian randomization (MR) is a genetic epidemiological method that uses genetic variation as an instrumental variable (IV) to explore the association between exposure and outcomes ¹³. Because genetic variables follow Mendel's law of random distribution, confounding factors and directional causality are effectively avoided.

2. Materials And Methods

We used two-sample MR to study the causal relationship between rheumatoid arthritis and the risk of pneumonia and its subtypes. All data were derived from publicly shared databases, and consent from participants was not needed. MR is based on three conditional assumptions. The first hypothesis is that the genetic variation selected as a tool variable is associated with exposure (RA). Second, genetic variation has nothing to do with known or unknown confounding factors. The final assumption is that genetic mutations affect the results only through exposure rather than through other means¹⁴.

3. Results

A total of 43 independent SNPs associated with RA were identified. The SNPs with incompatible alleles were removed. Finally, 42 SNPs were left, and corresponding information could be found for all four outcomes. More details are shown in Supplementary Table S1.

The associations of a genetically determined risk of RA with pneumonia and its subtypes using multiple MR methods are demonstrated in Fig. 1 & Fig. 2.

As seen, in all MR estimates, genetically predicted RA was causally associated with a decreased risk of pneumonia in Fig. 1. The results of the IVW method were very significant (OR, 1.056 for pneumonia per log-odds increment in RA risk, 95% CI 1.034–1.077; p = 1.87E-07). The results obtained with the MR–Egger method were also significant (OR, 1.05, 95% CI 1.013–1.079; p = 0.0086). The P values of the weighted median (OR, 1.04, 95% CI 1.010–1.070; p = 0.008), simple mode (OR, 1.057, 95% CI 1.006–1.112; p = 0.035) and weighted mode (OR, 1.041, 95% CI 1.014–1.069; p = 0.004) were all less than 0.05. Even though we used a corrected P value of 0.013, only the simple mode results were greater than 0.013.

According to Fig. 2, we found no causal link between RA and pneumonia (death) or pneumonia (28-day death in critical care). The inverse-variance weighted method showed a causal effect of genetically determined RA on pneumonia (critical care) [OR, 1.053, 95% CI 1.001–1.106; p = 0.044], as shown in Fig. 1. The simple mode demonstrated that there was a causal effect of genetically determined RA on pneumonia (critical care) [OR, 1.233, 95% CI 1.074–1.417; p = 0.005]. Estimates obtained from the weighted median, MR–Egger and weighted mode methods did not reveal an association between RA and pneumonia (critical care). There may be a causal link between RA and pneumonia (critical care), but the link must be considered with caution.

The results of MR-PRESSO analysis, MR–Egger intercept analysis and Cochran's Q test are displayed in Tables 1 & 2. The P values of the three tests were all greater than 0.05, which means that there was no heterogeneity or pluripotency in this study. A leave-one-out analysis did not find problematic SNPs, as shown in Supplementary Figures.

Pneumonia+：Pneumonia (death)；Pneumonia-：Pneumonia (critical care)；Pneumonia*：Pneumonia (28 day death in critical care)；

4. Discussion

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.

5. Conclusion

In summary, our MR analysis found evidence to support a causal relationship between RA and pneumonia. The results also showed that RA had no causal relationship with pneumonia (death) or pneumonia (28-day death in critical care). A causal link between RA and pneumonia (critical care) was observed, but the link must be considered with caution. In addition, additional clinical and experimental evidence is needed to confirm our findings and further clarify the mechanism.

Abbreviations

RA: Rheumatoid arthritis

SNPs: Single-nucleotide polymorphisms

GWAS: Genome-wide association study

IVW: Inverse-variance weighted

GBD: Global Burden of Diseases

MR: Mendelian randomization

IV: Instrumental variable

ORs: Odds ratios

CIs: Confidence intervals

Declarations

Authors' Contributions:

PL: writing-original draft. LL, WKH and KX: conceptualization, project administration, and writing-review and editing. PL and KX: data curation and methodology. PX and LL: formal analysis, validation, visualization and software. All authors contributed to the article and approved the submitted version.

Acknowledgements

Not applicable.

Conflict of Interest

None.

Funding

This work was supported by the National Natural Science Foundation of China (82072432, 81772410).

Data Availability Statement

Data used in the present study are all publicly available. Corresponding author will provide the data upon reasonable request.

Ethical Statement

There is no ethical statement here, because of all data downloaded from the Internet.

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