OP0284 Muc5b promoter variant rs35705950 is a risk factor for rheumatoid arthritis – interstitial lung disease

Abstract

BackgroundRheumatoid arthritis–associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) share phenotypic similarities. The gain-of-function MUC5B promoter variant rs35705950 is the strongest risk factor for development of IPFObjectivesWe hypothesised that rs35705950 would also contribute to the risk of ILD in RA patients.MethodsUsing a French discovery population and multi-ethnic validation populations from 6 different countries, we tested the association of the MUC5B promoter variant in RA-ILD (n=620), RA without ILD (n=614), and unaffected controls (n=5448).ResultsThe discovery population revealed an association of the MUC5B promoter variant with RA-ILD when compared to unaffected controls (ORadj=3.8 95% CI: 2.8 to 5.2; p=9.7x10–17) (figure 1A). Similar to the discovery cohort, the MUC5B promoter variant was significantly over-represented among the cases of RA-ILD in the multi-ethnic study cohorts when compared to unaffected controls (OR adj=5.5 95% CI: 4.2 to 7.2; p=4.7x10–35) (figure 1A), and when the discovery population and the multi-ethnic cohorts were combined (OR combined=4.7 95% CI: 3.9 to 5.8; p=1.3x10–49) (figure 1A). Additionally, the MUC5B promoter variant was found to increase the risk of ILD among patients with RA (OR combined=3.1 95% CI: 1.8 to 5.4; p=7.4x10–5), however, no statistical association with the MUC5B promoter variant was observed for RA without ILD (figure 1B). The association of the MUC5B promoter variant with RA-ILD increased significantly when restricted to the usual interstitial pneumonia (UIP) by high-resolution computed tomography (OR combined=6.1 95% CI: 2.9 to 13.1; p=2.5x10–6) (figure 1C). Immunohistochemical and in-situ hybridization analysis of RA-ILD lung tissue demonstrated expression of MUC5B by type 2 alveolar epithelial cells undergoing endoplasmic reticulum stress.ConclusionsOur findings demonstrate that MUC5B promoter variant rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of UIP.Disclosure of InterestNone declared

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality

“…The cohort demographics and a description of the clinical conditions for all genotyped MVP participants and COVID-19 positive MVP participants (18) that were evaluated in this study are shown in Table 1. (22), rheumatoid arthritis with interstitial lung disease (RA-ILD) (23) and idiopathic pulmonary fibrosis (IPF)diagnosis (24). These variables were derived from the data within two years prior to the index date of diagnosis (Table E1).…”

Revealing the Secrets of Idiopathic Pulmonary Fibrosis

“…Gene variants (rare and common sequence variants in 7 genes [MUC5B, TERT, TERC, RTEL1, PARN, SFTPC, and SFTPA2; [3][4][5][6][7][8][9][10][11] ] and in at least 12 novel loci 12,13 ), environmental exposures (asbestos and microorganisms), and immune conditions (rheumatoid arthritis and scleroderma; 14 ) place individuals at risk of developing the radiographic and pathological features of UIP. The more common risk factors, such as age, male sex, cigarette smoking, and the MUC5B promoter variant predispose individuals to develop phenocopies of IPF 3 , including rheumatoid arthritis associated interstitial lung disease (RA-ILD) 15 and chronic hypersensitivity pneumonitis 16 . The heterogeneity of IPF is highlighted further by the multiple emerging epigenetic 17 and transcriptional [18][19][20] profiles reported in this disease.…”

Developmental pathways of pulmonary abnormalities in rheumatoid arthritis according to sequential HRCT findings

“…In IIP, there is a type of ILD, respiratory bronchiolitis-associated ILD, which is associated with small airway inflammation (25). Moreover, recent studies found MUC5B promoter variant in patients with RA-UIP and IPF, but not in patients with RA without ILD (26). MUC5B is a mucin secreted by bronco-epithelial cells, hence a connection between AD and ILD in RA-ILD might be suggested.…”