1123: Excess of Rare Deleterious Variants Within JAK-STAT Pathway - Related Genes in Patients with Rheumatoid Arthritis Associated Interstitial Lung Disease

Pierre-Antoine Juge¹, Steven Gazal², Raphaël Borie³, Lidwine Wemeau⁴, Marie-Pierre Debray⁵, Sebastien Ottaviani⁶, Sylvain Marchand Adam⁷, Christophe Richez⁸, Hilario Nunes⁹, Pascal Richette¹⁰, Caroline Kannengiesser¹¹, Jérome Avouac¹², Jean Sibilia¹³, René-Marc Flipo¹⁴, Vincent Cottin¹⁵, Thierry Schaeverbeke¹⁶, Martin Soubrier¹⁷, Nathalie Saidenberg-Kermanac’h¹⁸, Dominique Valeyre¹⁹, Catherine Boileau¹¹, Bruno Crestani²⁰ and Philippe Dieude²¹, ¹Rheumatology department, Bichat Hospital, Paris, France, ²University of Southern California, Los Angeles, CA, ³Pulmonology department, Bichat Hospital, Paris, France, ⁴Pulmonology department, Lille University hospital, Lille, France, ⁵Radiology department, Hôpital Bichat, Paris, France, ⁶Hopital Bichat-Claude Bernard, Paris, France, ⁷Pulmonology department, Tours University Hospital, Tours, France, ⁸Université de Bordeaux, Bordeaux, France, ⁹Pulmonology department, Hopital Avicenne, Bobigny, France, ¹⁰Department of Rheumatology, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France, ¹¹Genetic Department, Bichat hospital, Paris, France, ¹²Rheumatology Department, Cochin hospital, Paris, France, ¹³University Hospital of Strasbourg, Strasbourg, France, ¹⁴Hôpital Roger Salengro, Lille, France, ¹⁵Coordinating Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, University of Lyon, INRAE, Lyon, France, ¹⁶FHU ACRONIM, University Hospital of Bordeaux, University of Bordeaux, Bordeaux, France, ¹⁷Gabriel-Montpied Hospital, Clermont-Ferrand, France, ¹⁸Rheumatology Department, Avicenne Hospital, Bobigny, France, ¹⁹Pulmonology department, Avicenne Hospital, Bobigny, France, ²⁰Hopital Bichat, Paris University, Paris, France, ²¹Université Paris Cité, Paris, France

Background/Purpose: Interstitial lung disease (ILD) is a leading cause of morbidity and mortality in patients with RA. To date, there are no specific treatments available for patients with RA-ILD. Several arguments suggest a potential role of the JAK-STAT signaling transduction pathway in the RA-ILD physiopathogenesis. Our objective was to test for association JAK-STAT pathway related genes rare coding variants with ILD in patients with RA.

Methods: In this candidate case-control genetic association study, RA-ILD patients were compared to RA-noILD patients. All cases fulfilled the 2010 EULAR-ACR and/or 1987 ACR revised criteria for RA. The ILD status was established by chest HRCT that were centrally reviewed by an experienced reader. Whole exome sequencing (WES) was performed, followed by a restricted analysis in JAK-STAT pathway candidate genes extracted from the Gene Ontology database. Two JAK-STAT related genes lists were generated, the first included 110 genes and a second restricted to 9 genes (STAT1, STAT2, STAT3, STAT4, STAT5, TYK2, JAK1, JAK2 and JAK3) for sensitivity analyses. Analyses were restricted to rare variants predicted to be deleterious: 1) variants with a minor allele frequency < 0.1% in non-Finnish Europeans of gnomAD, 2) variants predicted to have a high impact in the protein or to change protein effectiveness, 3) variants with a CADD score ≥ 15. Burden tests were performed using a logistic regression in 163 RA-ILD vs. 232 RA-noILD.

Results: 163 patients with RAILD and 235 with RA-noILD were included in the study. Briefly, RA-ILD patients were more frequently men (81.7% vs. 55.8%), elder at RA onset (64.3 ± 10.9 y/o vs. 44.1 ± 12.7 y/o) and more frequently smokers (60.0% vs. 48.4%). Restricted analysis on the 110 JAK-STAT candidates genes revealed an excess of rare variants in patients with RA-ILD when compared to patients with RA-noILD: 57.06% vs. 46.12%; OR=1.37 95% CI [1.12-1.69], P=2.56x10^-3 (Table1, Figure1). The sensitive analyze restricted to STAT1, STAT2, STAT3, STAT4, STAT5, TYK2, JAK1, JAK2 and JAK3 found significant excess of rare variants in patients with RA-ILD: OR=1.88 95% CI [1.06-3.57], P=0.04 (Table1, Figure1).

Conclusion: This discovery step study found an excess of rare variants predicted to be deleterious within JAK-STAT pathway related genes in patients with RA-ILD compared to patients with RA-noILD. These findings suggest that the JAK-STAT pathway could play a physiopathogenic role in the occurrence of RA-ILD.
Table 1

Figure 1
Disclosures: P. Juge, Bristol-Myers Squibb(BMS), Novartis, AstraZeneca, Boehringer-Ingelheim; S. Gazal, None; R. Borie, Roche, Boehringer-Ingelheim; L. Wemeau, Boehringer-Ingelheim, Bristol-Myers Squibb(BMS), Roche, Sanofi, Pfizer; M. Debray, None; S. Ottaviani, None; S. Marchand Adam, None; C. Richez, AbbVie/Abbott, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb(BMS), Galapados, GlaxoSmithKlein(GSK), Eli Lilly, Novartis, Pfizer; H. Nunes, None; P. Richette, AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB; C. Kannengiesser, None; J. Avouac, None; J. Sibilia, Bristol-Myers Squibb(BMS), Roche, AbbVie/Abbott, Roche, UCB, Novartis; R. Flipo, AbbVie/Abbott, Biogen, Bristol-Myers Squibb(BMS), Eli Lilly, Janssen, MSD, Mylan, Nordic Pharma France, Novartis, Pfizer, Roche-Chugaï, Sandoz, Sanofi, UCB; V. Cottin, Boehringer Ingelheim, Roche, Shionogi, RedX, PureTech, Celgene/BMS, AstraZeneca, XSL Behring, Sanofi, United Therapeutics, Pliant, Boehringer Ingelheim, Roche, Galapagos, Celgene/BMS, CSL Behring, Galecto, Fibrogen; T. Schaeverbeke, None; M. Soubrier, None; N. Saidenberg-Kermanac’h, None; D. Valeyre, None; C. Boileau, None; B. Crestani, Roche, Boehringer-Ingelheim; P. Dieude, None.