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Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study

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posted on 2024-06-03, 15:33 authored by Olivia C Leavy, Leticia Kawano-Dourado, Iain D Stewart, Jennifer K Quint, Joshua J Solomon, Raphael Borie, Bruno Crestani, Louise V Wain, Gisli Jenkins, Philippe Dieudé, Cosetta Minelli
BackgroundA usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors.MethodsWe used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions.FindingsIPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor.InterpretationOur findings support the hypothesis that RA-UIP may be due to a cause–effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.

History

Author affiliation

College of Life Sciences Population Health Sciences

Version

  • VoR (Version of Record)

Published in

Thorax

Volume

79

Pagination

538-544

Publisher

BMJ

issn

0040-6376

eissn

1468-3296

Copyright date

2024

Available date

2024-06-03

Spatial coverage

England

Language

en

Deposited by

Professor Louise Wain

Deposit date

2024-05-29

Data Access Statement

Data are available upon reasonable request. IPF GWAS data are available from: https://github.com/genomicsITER/PFgenetics. RA GWAS data are available from: https://www.decode.com/summarydata/.

Rights Retention Statement

  • No

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