Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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(telomeraseRNAcomponent),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: 2561 bp; 95% CI, 2933 to 2190; P = 0.003; replication: 2612 bp; 95% CI, 2870 to 2354; P = 5.3031026). 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.

Original languageEnglish (US)
Pages (from-to)1154-1163
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number9
DOIs
StatePublished - Nov 1 2019

Fingerprint

Extrinsic Allergic Alveolitis
Telomere
Confidence Intervals
Genes
Proteins
Leukocytes
Transplants
Survival
Poly A
Pulmonary Fibrosis
Telomerase
Ribonucleases
Proportional Hazards Models
Gene Frequency
Rheumatoid Arthritis
Polymerase Chain Reaction

Keywords

  • Alveolitis
  • Extrinsic allergic
  • Prognosis
  • Telomere

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis. / Ley, Brett; Torgerson, Dara G.; Oldham, Justin M.; Adegunsoye, Ayodeji; Liu, Shuo; Li, Jie; Elicker, Brett M.; Henry, Travis S.; Golden, Jeffrey A.; Jones, Kirk D.; Dressen, Amy; Yaspan, Brian L.; Arron, Joseph R.; Noth, Imre; Hoffmann, Thomas J.; Wolters, Paul J.

In: American journal of respiratory and critical care medicine, Vol. 200, No. 9, 01.11.2019, p. 1154-1163.

Research output: Contribution to journalArticle

Ley, B, Torgerson, DG, Oldham, JM, Adegunsoye, A, Liu, S, Li, J, Elicker, BM, Henry, TS, Golden, JA, Jones, KD, Dressen, A, Yaspan, BL, Arron, JR, Noth, I, Hoffmann, TJ & Wolters, PJ 2019, 'Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis', American journal of respiratory and critical care medicine, vol. 200, no. 9, pp. 1154-1163. https://doi.org/10.1164/rccm.201902-0360OC
Ley, Brett ; Torgerson, Dara G. ; Oldham, Justin M. ; Adegunsoye, Ayodeji ; Liu, Shuo ; Li, Jie ; Elicker, Brett M. ; Henry, Travis S. ; Golden, Jeffrey A. ; Jones, Kirk D. ; Dressen, Amy ; Yaspan, Brian L. ; Arron, Joseph R. ; Noth, Imre ; Hoffmann, Thomas J. ; Wolters, Paul J. / Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis. In: American journal of respiratory and critical care medicine. 2019 ; Vol. 200, No. 9. pp. 1154-1163.
@article{4ef070155d1d4f9d8dc4ae7548682801,
title = "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(telomeraseRNAcomponent),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: 2561 bp; 95{\%} CI, 2933 to 2190; P = 0.003; replication: 2612 bp; 95{\%} CI, 2870 to 2354; P = 5.3031026). 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.",
keywords = "Alveolitis, Extrinsic allergic, Prognosis, Telomere",
author = "Brett Ley and Torgerson, {Dara G.} and Oldham, {Justin M.} and Ayodeji Adegunsoye and Shuo Liu and Jie Li and Elicker, {Brett M.} and Henry, {Travis S.} and Golden, {Jeffrey A.} and Jones, {Kirk D.} and Amy Dressen and Yaspan, {Brian L.} and Arron, {Joseph R.} and Imre Noth and Hoffmann, {Thomas J.} and Wolters, {Paul J.}",
year = "2019",
month = "11",
day = "1",
doi = "10.1164/rccm.201902-0360OC",
language = "English (US)",
volume = "200",
pages = "1154--1163",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "9",

}

TY - JOUR

T1 - Rare protein-altering telomere-related gene variants in patients with chronic hypersensitivity pneumonitis

AU - Ley, Brett

AU - Torgerson, Dara G.

AU - Oldham, Justin M.

AU - Adegunsoye, Ayodeji

AU - Liu, Shuo

AU - Li, Jie

AU - Elicker, Brett M.

AU - Henry, Travis S.

AU - Golden, Jeffrey A.

AU - Jones, Kirk D.

AU - Dressen, Amy

AU - Yaspan, Brian L.

AU - Arron, Joseph R.

AU - Noth, Imre

AU - Hoffmann, Thomas J.

AU - Wolters, Paul J.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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(telomeraseRNAcomponent),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: 2561 bp; 95% CI, 2933 to 2190; P = 0.003; replication: 2612 bp; 95% CI, 2870 to 2354; P = 5.3031026). 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.

AB - 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(telomeraseRNAcomponent),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: 2561 bp; 95% CI, 2933 to 2190; P = 0.003; replication: 2612 bp; 95% CI, 2870 to 2354; P = 5.3031026). 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.

KW - Alveolitis

KW - Extrinsic allergic

KW - Prognosis

KW - Telomere

UR - http://www.scopus.com/inward/record.url?scp=85074377194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074377194&partnerID=8YFLogxK

U2 - 10.1164/rccm.201902-0360OC

DO - 10.1164/rccm.201902-0360OC

M3 - Article

C2 - 31268371

AN - SCOPUS:85074377194

VL - 200

SP - 1154

EP - 1163

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 9

ER -