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

Background Rheumatoid 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 IPF Objectives We hypothesised that rs35705950 would also contribute to the risk of ILD in RA patients. Methods Using 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). Results The discovery population revealed an association of the MUC5B promoter variant with RA-ILD when compared to unaffected controls (OR adj =3.8 95% CI: 2.8 to 5.2; p=9.7x10–1 7 ) (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=4.7x10–3 5 ) (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=1.3x10–4 9 ) (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. Conclusions Our findings demonstrate that MUC5B promoter variant rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of UIP. Disclosure of Interest None declared