Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the ,, or coding regions The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of ,, or mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10). Telomeres were shorter in RA-ILD patients with a , or mutation than in controls (p=2.87×10).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.
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
BackgroundDespite its high prevalence and mortality, little is known about the pathogenesis of RA–associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA–ILD frequently share the usual interstitial pneumonia pattern and common environmental risk factors, we hypothesized that the two diseases may share additional risk factors including FPF-linked genes.ObjectivesOur aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.MethodsWe used whole-exome sequencing (WES) followed by restricted analysis of a discrete number of FPF-linked genes and performed a Burden test to assess the excess number of mutations in RA–ILD patients compared to controls.ResultsAmong the 101 RA–ILD patients included, 12 (11.9%) had 13 WESidentified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA–ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations for RA–ILD patients (p=9.45’10-4, odds ratio [OR] 3.17 95% CI 1.53 – 6.12). Telomeres were shorter for RA-ILD patients with a TERT, RTEL1 or PARN mutation than controls (p=2.87x10-2).ConclusionsOur results support the contribution of FPF-linked genes to RA–ILD susceptibility.Disclosure of InterestNone declared
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