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Genetic Testing in Interstitial Lung Disease: Potential Benefits and Unintended Risks

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Abstract

Purpose of Review

This review aims to summarize the recent evidence supporting the role of genetic testing across the spectrum of interstitial lung diseases and identifying barriers and unintended risks of genetic testing.

Recent Findings

There is increasing interest among patients and their relatives in pursuing testing and no significant negative psychological impact of testing has been identified. Specific group of individuals who would most benefit from genetic testing (younger age at diagnosis, familial pulmonary fibrosis, features of short telomere syndrome, Hermansky-Pudlak syndrome, and relatives of individuals with known pathogenic genetic variants) and those who would likely not benefit from testing have been recently addressed. Gene sequencing can be used to identify known pathogenic variants in the surfactant-related genes and telomere-related genes. Peripheral blood leukocyte telomere length measurement may be of prognostic value and evidence for using this to guide clinical decision-making is evolving. Practical aspects like cost and availability of genetic testing are major barriers to genetic testing in the USA.

Summary

Though genetic testing is not currently a part of routine clinical practice, there is a role for testing in specific situations. Future research should focus on how the results of genetic testing can guide clinical decision-making in pulmonary fibrosis.

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References

  1. Selman M, Lin HM, Montano M, Jenkins AL, Estrada A, Lin Z, et al. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis. Hum Genet. 2003;113(6):542–50.

    Article  CAS  PubMed  Google Scholar 

  2. Crossno PF, Polosukhin VV, Blackwell TS, Johnson JE, Markin C, Moore PE, et al. Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC. Chest. 2010;137(4):969–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, et al. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med. 2010;182(11):1419–25.

    Article  PubMed  Google Scholar 

  4. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest. 2013;123(3):996–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Juge PA, Lee JS, Ebstein E, Furukawa H, Dobrinskikh E, Gazal S, et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N Engl J Med. 2018;379(23):2209–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ley B, Newton CA, Arnould I, Elicker BM, Henry TS, Vittinghoff E, et al. The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med. 2017;5(8):639–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, et al. MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med. 2013;368(23):2192–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Putman RK, Gudmundsson G, Araki T, Nishino M, Sigurdsson S, Gudmundsson EF, et al. The MUC5B promoter polymorphism is associated with specific interstitial lung abnormality subtypes. Eur Respir J. 2017;50(3).

  10. Grant-Orser A, Avitzur N, Morisset J, Fell CD, Johannson KA. Perceptions of genetic testing: a mixed-methods study of patients with pulmonary fibrosis and their first-degree relatives. Ann Am Thorac Soc. 2022;19(8):1305–12.

    Article  PubMed  Google Scholar 

  11. Garcia-Sancho C, Buendia-Roldan I, Fernandez-Plata MR, Navarro C, Perez-Padilla R, Vargas MH, et al. Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis. Respir Med. 2011;105(12):1902–7.

    Article  PubMed  Google Scholar 

  12. Cutting CC, Bowman WS, Dao N, Pugashetti JV, Garcia CK, Oldham JM, et al. Family History of pulmonary fibrosis predicts worse survival in patients with interstitial lung disease. Chest. 2021;159(5):1913–21.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Kropski JA, Young LR, Cogan JD, Mitchell DB, Lancaster LH, Worrell JA, et al. Genetic Evaluation and testing of patients and families with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2017;195(11):1423–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McGroder CF, Zhang D, Choudhury M, Podolanczuk AJ, Lederer D, Hoffman EA, et al. Radiographic lung abnormalities in first-degree relatives of patients with different subtypes of pulmonary fibrosis. Chest. 2023.

  15. Hunninghake GM, Quesada-Arias LD, Carmichael NE, Martinez Manzano JM, Poli De Frias S, Baumgartner MA, et al. Interstitial lung disease in relatives of patients with pulmonary fibrosis. Am J Respir Crit Care Med. 2020;201(10):1240–8.

  16. Krauss E, Gehrken G, Drakopanagiotakis F, Tello S, Dartsch RC, Maurer O, et al. Clinical characteristics of patients with familial idiopathic pulmonary fibrosis (f-IPF). BMC Pulm Med. 2019;19(1):130.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Peljto AL, Zhang Y, Fingerlin TE, Ma SF, Garcia JG, Richards TJ, et al. Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA. 2013;309(21):2232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Putman RK, Gudmundsson G, Axelsson GT, Hida T, Honda O, Araki T, et al. Imaging patterns are associated with interstitial lung abnormality progression and mortality. Am J Respir Crit Care Med. 2019;200(2):175–83.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Araki T, Putman RK, Hatabu H, Gao W, Dupuis J, Latourelle JC, et al. Development and progression of interstitial lung abnormalities in the framingham heart study. Am J Respir Crit Care Med. 2016;194(12):1514–22.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hida T, Nishino M, Hino T, Lu J, Putman RK, Gudmundsson EF, et al. Traction bronchiectasis/bronchiolectasis is associated with interstitial lung abnormality mortality. Eur J Radiol. 2020;129: 109073.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Putman RK, Hatabu H, Araki T, Gudmundsson G, Gao W, Nishino M, et al. Association Between interstitial lung abnormalities and all-cause mortality. JAMA. 2016;315(7):672–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hobbs BD, Putman RK, Araki T, Nishino M, Gudmundsson G, Gudnason V, et al. Overlap of genetic risk between interstitial lung abnormalities and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(11):1402–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Putman RK, Axelsson GT, Ash SY, Sanders JL, Menon AA, Araki T, et al. Interstitial lung abnormalities are associated with decreased mean telomere length. Eur Respir J. 2022;60(2).

  24. Oldham JM, Ma SF, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA, et al. TOLLIP, MUC5B, and the response to N-acetylcysteine among individuals with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2015;192(12):1475–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Alder JK, Armanios M. Telomere-mediated lung disease. Physiol Rev. 2022;102(4):1703–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gansner JM, Rosas IO. Telomeres in lung disease. Transl Res. 2013;162(6):343–52.

    Article  CAS  PubMed  Google Scholar 

  27. Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178(7):729–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Snetselaar R, van Moorsel CHM, Kazemier KM, van der Vis JJ, Zanen P, van Oosterhout MFM, et al. Telomere length in interstitial lung diseases. Chest. 2015;148(4):1011–8.

    Article  PubMed  Google Scholar 

  29. Stuart BD, Lee JS, Kozlitina J, Noth I, Devine MS, Glazer CS, et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir Med. 2014;2(7):557–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Newton CA, Batra K, Torrealba J, Kozlitina J, Glazer CS, Aravena C, et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur Respir J. 2016;48(6):1710–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ley B, Liu S, Elicker BM, Henry TS, Vittinghoff E, Golden JA, et al. Telomere length in patients with unclassifiable interstitial lung disease: a cohort study. Eur Respir J. 2020;56(2).

  32. Hoffman TW, van der Vis JJ, Biesma DH, Grutters JC, van Moorsel CHM. Extrapulmonary manifestations of a telomere syndrome in patients with idiopathic pulmonary fibrosis are associated with decreased survival. Respirology. 2022;27(11):959–65.

    Article  PubMed  Google Scholar 

  33. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A. 2008;105(35):13051–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Alder JK, Hanumanthu VS, Strong MA, DeZern AE, Stanley SE, Takemoto CM, et al. Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci U S A. 2018;115(10):E2358–65.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Antoniou KM, Walsh SL, Hansell DM, Rubens MR, Marten K, Tennant R, et al. Smoking-related emphysema is associated with idiopathic pulmonary fibrosis and rheumatoid lung. Respirology. 2013;18(8):1191–6.

    Article  PubMed  Google Scholar 

  36. Salisbury ML, Hewlett JC, Ding G, Markin CR, Douglas K, Mason W, et al. Development and progression of radiologic abnormalities in individuals at risk for familial interstitial lung disease. Am J Respir Crit Care Med. 2020;201(10):1230–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cottin V, Selman M, Inoue Y, Wong AW, Corte TJ, Flaherty KR, et al. Syndrome of combined pulmonary fibrosis and emphysema: an official ATS/ERS/JRS/ALAT research statement. Am J Respir Crit Care Med. 2022;206(4):e7–41.

    Article  PubMed  Google Scholar 

  38. Bellou V, Belbasis L, Evangelou E. Tobacco smoking and risk for pulmonary fibrosis: a prospective cohort study from the UK Biobank. Chest. 2021;160(3):983–93.

    Article  PubMed  Google Scholar 

  39. Copeland CR, Donnelly EF, Mehrad M, Ding G, Markin CR, Douglas K, et al. The association between exposures and disease characteristics in familial pulmonary fibrosis. Ann Am Thorac Soc. 2022;19(12):2003–12.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Copeland CR, Collins BF, Salisbury ML. Identification and remediation of environmental exposures in patients with interstitial lung disease: evidence review and practical considerations. Chest. 2021;160(1):219–30.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Goobie GC, Carlsten C, Johannson KA, Khalil N, Marcoux V, Assayag D, et al. Association of particulate matter exposure with lung function and mortality among patients with fibrotic interstitial lung disease. JAMA Intern Med. 2022;182(12):1248–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. McGroder CF, Zhang D, Choudhury MA, Salvatore MM, D’Souza BM, Hoffman EA, et al. Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length. Thorax. 2021;76(12):1242–5.

    Article  PubMed  Google Scholar 

  43. Cameli P, Alonzi V, d'Alessandro M, Bergantini L, Pordon E, Guerrieri M, et al. The effectiveness of nintedanib in patients with idiopathic pulmonary fibrosis, familial pulmonary fibrosis and progressive fibrosing interstitial lung diseases: a real-world study. Biomedicines. 2022;10(8).

  44. Justet A, Klay D, Porcher R, Cottin V, Ahmad K, Molina Molina M, et al. Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation. Eur Respir J. 2021;57(2).

  45. Flaherty KR, Wells AU, Cottin V, Devaraj A, Inoue Y, Richeldi L, et al. Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial. Eur Respir J. 2022;59(3).

  46. Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020;8(5):453–60.

    Article  CAS  PubMed  Google Scholar 

  47. Newton CA, Oldham JM, Ley B, Anand V, Adegunsoye A, Liu G, et al. Telomere length and genetic variant associations with interstitial lung disease progression and survival. Eur Respir J. 2019;53(4).

  48. Faust HE, Golden JA, Rajalingam R, Wang AS, Green G, Hays SR, et al. Short lung transplant donor telomere length is associated with decreased CLAD-free survival. Thorax. 2017;72(11):1052–4.

    Article  PubMed  Google Scholar 

  49. Newton CA, Kozlitina J, Lines JR, Kaza V, Torres F, Garcia CK. Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival. J Heart Lung Transplant. 2017;36(8):845–53.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Esposito AJ, El-Chemaly SY. Lung transplant in familial pulmonary fibrosis: the road ahead. J Bras Pneumol. 2020;46(6): e20200487.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Planas-Cerezales L, Arias-Salgado EG, Berastegui C, Montes-Worboys A, Gonzalez-Montelongo R, Lorenzo-Salazar JM, et al. Lung transplant improves survival and quality of life regardless of telomere dysfunction. Front Med (Lausanne). 2021;8: 695919.

    Article  PubMed  Google Scholar 

  52. Newton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, et al. Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(3):336–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Podolanczuk AJ, Kim JS, Cooper CB, Lasky JA, Murray S, Oldham JM, et al. Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial. BMC Pulm Med. 2022;22(1):475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Klay D, Grutters JC, van der Vis JJ, Platenburg M, Kelder JC, Tromp E, et al. Progressive disease with low survival in adult patients with pulmonary fibrosis carrying surfactant-related gene mutations: an observational study. Chest. 2023;163(4):870–80.

    Article  CAS  PubMed  Google Scholar 

  55. van Moorsel CHM, van der Vis JJ, Grutters JC. Genetic disorders of the surfactant system: focus on adult disease. Eur Respir Rev. 2021;30(159).

  56. Salerno T, Peca D, Menchini L, Schiavino A, Boldrini R, Esposito F, et al. Surfactant protein C-associated interstitial lung disease; three different phenotypes of the same SFTPC mutation. Ital J Pediatr. 2016;42:23.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84(1):52–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68.

  59. Borie R, Kannengiesser C, Dupin C, Debray MP, Cazes A, Crestani B. Impact of genetic factors on fibrosing interstitial lung diseases. Incidence and clinical presentation in adults. Presse Med. 2020;49(2):104024.

  60. Borie R, Kannengiesser C, Antoniou K, Bonella F, Crestani B, Fabre A, et al. European Respiratory Society statement on familial pulmonary fibrosis. Eur Respir J. 2022.

  61. Newton CA, Oldham JM, Applegate C, Carmichael N, Powell K, Dilling D, et al. The Role of genetic testing in pulmonary fibrosis: a perspective from the Pulmonary Fibrosis Foundation Genetic Testing Work Group. Chest. 2022;162(2):394–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Carmichael N, Martinez Manzano JM, Quesada-Arias LD, Poli SF, Baumgartner MA, Planchart Ferretto MA, et al. Psychological impact of genetic and clinical screening for pulmonary fibrosis on asymptomatic first-degree relatives of affected individuals. Thorax. 2021;76(6):621–3.

    Article  PubMed  Google Scholar 

  63. Wang H, Zhuang Y, Peng H, Cao M, Li Y, Xu Q, et al. The relationship between MUC5B promoter, TERT polymorphisms and telomere lengths with radiographic extent and survival in a Chinese IPF cohort. Sci Rep. 2019;9(1):15307.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Peljto AL, Blumhagen RZ, Walts AD, Cardwell J, Powers J, Corte TJ, et al. Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants. Am J Respir Crit Care Med. 2023.

  65. Peljto AL, Selman M, Kim DS, Murphy E, Tucker L, Pardo A, et al. The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries. Chest. 2015;147(2):460–4.

    Article  PubMed  Google Scholar 

  66. Dhooria S, Bal A, Sehgal IS, Prasad KT, Kashyap D, Sharma R, et al. MUC5B Promoter polymorphism and survival in Indian patients with idiopathic pulmonary fibrosis. Chest. 2022;162(4):824–7.

    Article  CAS  PubMed  Google Scholar 

  67. Salisbury ML, Markin CR, Wu P, Cogan JD, Mitchell DB, Liu Q, et al. Peripheral blood telomere attrition in persons at risk for familial pulmonary fibrosis. Am J Respir Crit Care Med. 2023;207(2):208–11.

    Article  PubMed  Google Scholar 

  68. Adegunsoye A, Newton CA, Oldham JM, Ley B, Lee CT, Linderholm AL, et al. Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts. Nat Commun. 2023;14(1):1489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Armanios M. The Role of telomeres in human disease. Annu Rev Genomics Hum Genet. 2022;23:363–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. van der Vis JJ, van der Smagt JJ, van Batenburg AA, Goldschmeding R, van Es HW, Grutters JC, et al. Pulmonary fibrosis in non-mutation carriers of families with short telomere syndrome gene mutations. Respirology. 2021;26(12):1160–70.

    Article  PubMed  Google Scholar 

  71. Adegunsoye A, Morisset J, Newton CA, Oldham JM, Vittinghoff E, Linderholm AL, et al. Leukocyte telomere length and mycophenolate therapy in chronic hypersensitivity pneumonitis. Eur Respir J. 2021;57(3).

  72. Chen C, Wang R, Yuan Y, Li J, Yu X. Clinical features and novel genetic variants associated with Hermansky-Pudlak syndrome. Genes (Basel). 2022;13(7).

  73. Introne WJ, Huizing M, Malicdan MCV, O'Brien KJ, Gahl WA. Hermansky-Pudlak syndrome. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al. editors. GeneReviews((R)). Seattle (WA)1993.

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  1. Division of Pulmonary Critical Care Medicine, Medical University of South Carolina, 96 Jonathan Lucas Dr., MSC 630, 29425, Charleston, SC, USA

    Rachana Krishna

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  1. Rachana Krishna
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Dr. Krishna reports receiving institutional funds for serving as Site Principal Investigator for multisite clinical trials with United Therapeutics and from Biobridge Therapeutics, outside the submitted work.

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Krishna, R. Genetic Testing in Interstitial Lung Disease: Potential Benefits and Unintended Risks. Curr Pulmonol Rep 12, 228–238 (2023). https://doi.org/10.1007/s13665-023-00322-z

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