Contribution of Rare Deleterious Exonic Variants in Telomere Related Genes to Interstitial Lung Disease Risk in Patients with Rheumatoid Arthritis

Pierre-Antoine Juge¹, Leticia Kawano-Dourado², Steven Gazal³, Gregory McDermott⁴, Keigo Hayashi⁴, Jing Cui⁵, Marie-Pierre Debray⁶, Lidwine Stervinou-Wemeau⁷, Syvain Marchand-Adam⁸, Christophe Richez⁹, Hilario Nunes¹⁰, Jérôme Avouac¹¹, Rene-Marc Flipo¹², Vincent Cottin¹³, Martin Soubrier¹⁴, Nathalie Saidenberg Kermanac'h¹⁰, Caroline Kannengiesser¹⁵, Raphael Borie¹⁶, Bruno Crestani¹⁷, Tracy J. Doyle⁴, Soumya Raychaudhuri⁴, Elizabeth Karlson⁴, Jeffrey Sparks¹⁸ and Philippe Dieudé¹⁹, ¹Division of Rheumatology, Inflammation, and Immunity Brigham & Women's Hospital, Boston, MA, ²Hospital do Coração (HCor), São Paulo, Brazil, ³University of South California, Los Angeles, CA, ⁴Brigham and Women's Hospital, Boston, MA, ⁵Brigham and Women's Hospital, Boston, MA, ⁶CHU Bichat, Radiology, Paris, France, ⁷CHRU de Lille, Lille, France, ⁸CHU Tours, Tours, France, ⁹Université de Bordeaux, Bordeaux, France, ¹⁰CHU Avicenne, Bobigny, France, ¹¹Service de Rhumatologie, Hôpital Cochin, AP-HP.Centre – Université Paris Cité, Paris, France, ¹²La Lettre du Rhumatologue, Paris, France, ¹³Coordinating Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, University of Lyon, INRAE, Lyon, France, ¹⁴Gabriel-Montpied Hospital, Clermont-ferrand, France, ¹⁵CHU Bichat, Paris, France, ¹⁶Bichat-Claude Bernard, Universite de Paris, Paris, France, ¹⁷Hopital Bichat, Paris University, Paris, France, ¹⁸Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, ¹⁹Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, INSERM UMR1152, University de Paris Cité, Department of Rheumatology, Paris, France

Meeting: ACR Convergence 2023

Keywords: genetics, interstitial lung disease, rheumatoid arthritis

Session Information

Date: Tuesday, November 14, 2023

Title: (2095–2140) RA – Diagnosis, Manifestations, and Outcomes Poster III

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: RA-associated interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) share genetic risk factors such as MUC5B rs35705950. The exact role of telomere related genes (TRG) in the RA-ILD genetic background is unclear. A previous work found an excess of TRG rare deleterious variants in RA-ILD compared to healthy controls but did not allow to conclude without a control population of patients with RA without ILD. Our aim was to test for association TRG rare deleterious exonic variants with ILD in patients with RA.

Methods: This genetic case-control association study was composed of a derivation (France) and a replication (US) population. Cases with RA-ILD and controls with RA without ILD (RA-noILD) that had whole exome sequencing (WES) data were included. ILD status and pattern (usual interstitial pattern, UIP or non-UIP) was determined by review of clinically-indicated high-resolution computed tomography (HRCT) chest imaging. Rare deleterious exonic variants from 14 candidate TRG previously associated with pulmonary fibrosis (TERT, TERC, PARN, RTEL1, CTC1, TINF2, ACD, POT1, NAF1, ZCCHC8, NHP2, NOP10, WRAP53, and DKC1) were selected using 1) a reported frequency in gnomAD database < 0.1%, 2) a deleterious impact predicted by SIFT, POLYPHEN-2, and 3) a CADD score > 15. Proportions of variants carriers in RA-ILD and RA-noILD were compared using a classical burden test adjusted for sex, age at RA, RA duration, MUC5B rs3570590 genotype and a principal component analysis using ancestry informative markers. Results were combined in a meta-analysis.

Results: The French derivation dataset included 388 patients, 157 cases (40.5%), mean age at ILD or last normal HRTC 60.1 years, 273 female (70.4%); Table 1. 22 rare deleterious variants were identified in 13/157 cases (8.3%) and 8/231 controls (3.5%). The burden test suggested an excess of TRG rare variants in RA-ILD (OR 2.83, 95% CI 0.96-8.58; p=0.06); (Table 2, Figure 1). A significant association was observed for usual interstitial pneumonia (UIP) HRCT pattern (OR 4.66, 95% CI 1.27-16.86; p=0.02) whereas no association was detected for patients with RA-ILD and a non-UIP HRCT patterns (OR 2.14, 95% CI 0.48-8.26; p=0.29). The US replication dataset included 390 patients, 85 cases (21.8%), mean age at ILD or last normal HRCT was 61.4 years and 74.4% were female. Similar trend for an excess of TRG rare variants was observed with 28 variants identified in 9/85 cases and 19/305 controls (10.5% vs 6.2%, OR 1.83, 95% CI 0.72-4.33; p=0.18); (Table 2, Figure 1). Like in the derivation population, the excess of rare variants was more pronounced for RA-UIP: 13.8% vs 6.2% (OR 2.26, 95% CI 0.48-8.53; p=0.26) The meta-analysis provide evidence for a significant contribution of TRGs rare variants to RA-ILD (OR 2.16, 95% CI 1.09-4.26; p=0.03), more specifically for the UIP pattern (OR 3.28, 95% CI 1.30-8.27; p=0.01). No significant association was found for non-UIP patterns in the meta-analysis (OR 1.77, 95% CI 0.79-3.96; p=0.16).

Conclusion: TRG rare deleterious exonic variants contribute to the risk of ILD in patients with RA, more specifically in RA-UIP. These results confirmed the shared genetic architecture between RA-ILD and IPF.

Table 1. Characteristics of the included patients
ACPA: anti-citrullinated peptides antibodies; HRCT: high resolution computed tomography; ILD: interstitial lung disease; MAF: minor allele frequency; RF: rheumatoid factor; UIP: usual interstitial pneumonia.

Table 2. Classical burden test comparing the frequency of TRG rare deleterious variants in patients with RA-ILD (cases) and patients with RA-noILD (controls).
ILD: interstitial lung disease, OR [95% IC]: Odd ratios with 95% confidence interval; TRGs: telomere related genes; UIP: usual interstitial pneumonia.

Figure 1. Results from the Burden test assessing TRG rare deleterious variants contribution in RA-ILD.
Forest plot of odds ratios (OR) and 95% confidence intervals (CI). The boxes indicate OR, and the horizontal lines indicate 95% CI for the burden test comparing frequency of telomere related genes (TRG) rare deleterious exonic variants carriers in cases vs controls.

Disclosures: P. Juge: None; L. Kawano-Dourado: None; S. Gazal: None; G. McDermott: None; K. Hayashi: None; J. Cui: None; M. Debray: None; L. Stervinou-Wemeau: None; S. Marchand-Adam: None; C. Richez: AbbVie/Abbott, 2, 6, Amgen, 6, AstraZeneca, 2, 6, Bristol-Myers Squibb(BMS), 6, Eli Lilly, 6, 12, receipt of drugs, GlaxoSmithKlein(GSK), 2, 6, Novartis, 2, 6, Pfizer, 2, 6; H. Nunes: None; J. Avouac: AbbVie, 6, AstraZeneca, 6, Biogen, 6, BMS, 5, 6, Fresenius Kabi, 5, 6, Galapagos, 5, 6, Janssen, 6, Lilly, 6, Medac, 6, MSD, 6, Nordic Pharma, 6, Novartis, 6, Novartis (Dreamer), 5, Pfizer, 6, Pfizer (Passerelle), 5, Roche-Chugai, 6, Sandoz, 6, Sanofi, 6; R. Flipo: AbbVie, 2, Bristol-Myers Squibb(BMS), 2, Eli Lilly, 2, Janssen, 2, Medac, 2, MSD, 2, Nordic Pharma, 2, Novartis, 2, Pfizer, 2, Roche-Chugaï, 2, Sandoz, 2, Sanofi, 2; V. Cottin: Boehringer Ingelheim, 2, 5, 6, 12, Support for attending meetings, Celgene/BMS, 1, 2, CSL Behring, 2, Ferrer, 2, 6, 12, Support for attending meetings, FibroGen, 1, Galapagos, 1, 2, Galecto, 1, GlaxoSmithKline, 2, Pliant, 2, Pure Tech, 2, Redx, 2, Roche, 1, 2, 6, 12, Support for attending meetings, Sanofi, 2, Shionogi, 2; M. Soubrier: None; N. Saidenberg Kermanac'h: None; C. Kannengiesser: None; R. Borie: None; B. Crestani: None; T. Doyle: None; S. Raychaudhuri: AbbVie, 6, Janssen, 1, Mestag, Inc, 2, 8, Pfizer, 1, Sanofi, 1, Sonoma, 1, 8; E. Karlson: None; J. Sparks: AbbVie, 2, Amgen, 2, Boehringer Ingelheim, 2, Bristol-Myers Squibb, 2, 5, Gilead, 2, Inova Diagnostics, 2, Janssen, 2, Optum, 2, Pfizer, 2, ReCor, 2; P. Dieudé: AbbVie, 2, 6, Boehringer Ingelheim, 1, 2, 6, Bristol-Myers Squibb, 1, 2, 5, 6, Chugai, 5, Galapagos, 5, 6, Janssen, 2, 6, Novartis, 2, Pfizer, 1, 2, 5, 6.

To cite this abstract in AMA style:

Juge P, Kawano-Dourado L, Gazal S, McDermott G, Hayashi K, Cui J, Debray M, Stervinou-Wemeau L, Marchand-Adam S, Richez C, Nunes H, Avouac J, Flipo R, Cottin V, Soubrier M, Saidenberg Kermanac'h N, Kannengiesser C, Borie R, Crestani B, Doyle T, Raychaudhuri S, Karlson E, Sparks J, Dieudé P. Contribution of Rare Deleterious Exonic Variants in Telomere Related Genes to Interstitial Lung Disease Risk in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/contribution-of-rare-deleterious-exonic-variants-in-telomere-related-genes-to-interstitial-lung-disease-risk-in-patients-with-rheumatoid-arthritis/. Accessed .

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