Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.

Abstract

Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10-6). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

• Authors: Brett Ley, Dara G Torgerson, Justin M Oldham, Ayodeji Adegunsoye, Shuo Liu, Jie Li, Brett M Elicker, Travis S Henry, Jeffrey A Golden, Kirk D Jones, Amy Dressen, Brian L Yaspan, Joseph R Arron, Imre Noth, Thomas J Hoffmann, Paul J Wolters
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 200 Issue 9 Pg. 1154-1163 (11 01 2019) ISSN: 1535-4970 [Electronic] United States
• PMID: 31268371 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DKC1 protein, human
• Nuclear Proteins
• Shelterin Complex
• TERF1 protein, human
• Telomere-Binding Proteins
• telomerase RNA
• RNA
• Telomerase
• Exoribonucleases
• poly(A)-specific ribonuclease
• RTEL1 protein, human
• DNA Helicases

Topics

• Aged
• Alveolitis, Extrinsic Allergic (genetics)
• Case-Control Studies
• Cell Cycle Proteins (genetics)
• Cohort Studies
• DNA Helicases (genetics)
• Exoribonucleases (genetics)
• Female
• Humans
• Male
• Middle Aged
• Mutation (genetics)
• Nuclear Proteins (genetics)
• RNA (genetics)
• Shelterin Complex
• Telomerase (genetics)
• Telomere (genetics)
• Telomere-Binding Proteins (genetics)