AB0007 Shared genetic predisposition in rheumatoid arthritis–interstitial lung disease and familial pulmonary fibrosis

Abstract

Background: Despite 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. Objectives: Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. Methods: 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. Results: Among 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). Conclusions: Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.