POS0593 CONTRIBUTION OF RARE EXONIC VARIANTS IN TELOMERE-RELATED GENES TO INTERSTITIAL LUNG DISEASE RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS AND IDIOPATHIC PULMONARY FIBROSIS
Authors: P. A. Juge, L. Kawano-Dourado, A. Stockwell, J. S. Lee, S. Gazal, G. Mcdermott, K. Hayashi, J. Cui, B. Granger, C. Kannengiesser, R. Borie, L. Wemeau Stervinou, M. P. Debray, P. J. Wolters, S. Marchand-Adam, C. Richez, H. Nunes, P. Froguel, J. Avouac, R. M. Flipo, V. Cottin, M. C. Boissier, T. Schaeverbeke, N. Saidenberg Kermanac’h, B. Crestani, T. Doyle, S. Raychaudhuri, E. Karlson, B. L. Yaspan, P. Dieudé
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> RA-associated interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) share the <i>MUC5B</i> rs35705950 genetic risk factor and a predilection for the usual interstitial pneumonia (UIP) pattern. The role of telomere-related genes (TRGs) in the RA-ILD genetic background is unclear. Previous work found an excess of TRG rare exonic variants in RA-ILD compared to healthy controls. However, lack of RA controls without ILD precluded an investigation of whether the enrichment for rare variants in TRGs was associated with the RA or ILD pattern. <h3>Objectives:</h3> To investigate the contribution of TRG rare variants to ILD vs. no ILD in patients with RA, and to IPF vs. healthy controls. <h3>Methods:</h3> For the RA analyses, this genetic case-control association study consisted of a derivation (France) and a replication (US) sample that included cases with RA-ILD and controls with RA without ILD (RA-noILD). For the IPF analyses, cases with IPF were compared to healthy controls without IPF. Whole exome or genome sequencing was performed in all participants. ILD status and pattern (UIP or non-UIP) was determined by review of clinically-indicated high-resolution computed tomography (HRCT) chest imaging. Exonic variants from 14 candidate TRGs previously associated with IPF or linked to familial pulmonary fibrosis (<i>TERT, TERC, PARN, RTEL1, CTC1, TINF2, ACD, POT1, NAF1, ZCCHC8, NHP2, NOP10, WRAP53,</i> and <i>DKC1</i>) were identified and annotated for their frequency by gnomAD database and their functional impact using predictive tools (SIFT, POLYPHEN-2, and CADD score). Telomere length (TL) was measured in RA cases and controls from the derivation sample, in IPF cases and in non-IPF healthy controls. TRG rare variants enrichment in cases and controls was compared using the classical burden test adjusted for sex, age at RA, RA duration, <i>MUC5B</i> rs35705950 genotype and principal component of ancestry. Derivation and replication results were combined and meta-analyzed. We performed sub-group analyses restricted to cases with TL &lt; 10<sup>th</sup> percentile. <h3>Results:</h3> In the RA analyses, the derivation sample included 157 RA-ILD cases and 231 RA-noILD controls, and the replication sample included 85 RA-ILD cases and 305 RA-noILD controls; Table 1. In the derivation sample, we identified 19 distinct rare TRG variants carried by 13/157 RA-ILD cases and 8/231 RA-noILD controls (8.3% vs. 3.5%, OR 2.83, 95% CI 0.96-8.58; p=0.06); Table 2. In the replication sample, an enrichment of TRG rare variants was also observed in RA-ILD cases (9/85 [10.6%] compared to 18/305 [5.9%] in RA-noILD controls, Burden test p=0.20), reaching statistical significance in the meta-analysis analysis (OR 2.12, 95% CI 1.07-4.21, p=0.03). When restricting the analyses to RA-UIP cases, we found a greater enrichment of TRG rare variants in both derivation and replication samples (10.5% and 13.8%, respectively) leading to a significant association with RA-UIP (OR 3.17, 95% CI 1.37-7.32, p=0.007), whereas no association was detected with non-UIP RA-ILD (p=0.33). Similar to RA-ILD and RA-UIP, the analysis of 1277 IPF cases and 1874 non-IPF healthy controls, found a significant excess of rare variants in TRG comparing patients with IPF to healthy controls: 2.0% vs. 1.5%, OR 2.31, 95% CI 1.24-4.37, p=0.013. No interaction between TRG rare variants and smoking status nor <i>MUC5B</i> rs35705950 was detected. When restricting to patients with RA-ILD having a TL&lt;10th percentile, we observed a significant enrichment of TRG rare variants with an increased risk: 10.0% vs. 3.5%, OR 5.93, 95% CI 1.28-26.30, p=0.04. Similar to that observed in RA-ILD, when restricting the analysis to the IPF cases having a TL&lt;10<sup>th</sup> percentile, a significant excess of TRG rare variants was detected (5.5% vs. 1.5%, OR 6.09 95% CI 2.58-13.50, p=0.0002). <h3>Conclusion:</h3> In aggregate, our findings provide proof of a contribution of TRGs to ILD risk in RA. Like <i>MUC5B</i> rs35705950, the excess of TRG rare variants support the paradigm of a shared genetic background between RA-ILD and IPF. Similar to IPF, our results indicates that the short TL observed in RA-ILD can be partially attributed to TRG rare variants. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>REFERENCES: NIL. Acknowledgements:</h3> Société Française de Rhumatologie. <h3>Disclosure of Interests:</h3> <b>None declared.</b>