Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Clonal Hematopoiesis of Indeterminate Potential Is Associated with Current Smoking Status and History of Exacerbation in Patients with Chronic Obstructive Pulmonary Disease

  • Jung-Kyu Lee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center) ;
  • Hongyul An (Genome Opinion Inc.) ;
  • Youngil Koh (Genome Opinion Inc.) ;
  • Chang-Hoon Lee (Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital)
  • Received : 2023.10.17
  • Accepted : 2024.02.06
  • Published : 2024.07.31
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Abstract

Background: There is limited data regarding the clinical outcomes of clonal hematopoiesis of indeterminate potential (CHIP) in patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the clinical significance of CHIP as a COPD biomarker. Methods: This retrospective study was conducted on patients with COPD who were enrolled prospectively in the Seoul National University Hospital Airway Registry from January 2013 to December 2019 and underwent pulmonary function and blood tests. We evaluated the CHIP score according to smoking status and severity of airflow obstruction. Results: We analyzed next-generation sequencing data to detect CHIP in 125 patients with COPD. Current smokers had a higher prevalence of CHIP in combination of DNMT3A, TET2, and PPM1D (DTP), DNA methyltransferase 3 alpha (DNMT3A), and protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) genes than in never- or ex-smokers. CHIP of DTP and DNMT3A genes was significantly associated with current smokers (adjusted odds ratio [aOR], 2.80; 95% confidence interval [CI], 1.01 to 7.79) (aOR, 4.03; 95% CI, 1.09 to 14.0). Patients with moderate-to-severe airflow obstruction had a higher prevalence of CHIP in most of the explored genes than those with mild obstruction, although the difference was not statistically significant. CHIP in ASXL transcriptional regulator 1 (ASXL1) genes was significantly associated with history of mild, severe, and total acute exacerbation. Conclusion: Given that CHIP in specific genes was significantly associated with current smoking status and acute exacerbation, CHIP can be considered as a candidate biomarker for COPD patients.

Keywords

Acknowledgement

The biospecimens and data used in this study were provided by the Biobank of Seoul National University Hospital, a member of Korea Biobank Network (KBN4_A03). Quantitative measurement of CHIP was performed through targeted sequencing using the BloodSafe test (Genome Opinion, Seoul, Republic of Korea).

References

  1. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015;126:9-16. 
  2. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014;371:2488-98. 
  3. Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017;355:842-7. 
  4. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017;377:111-21. 
  5. Shivarov V, Ivanova M. Clonal haematopoiesis and COVID-19: a possible deadly liaison. Int J Immunogenet 2020;47:329-31. 
  6. Berry CE, Wise RA. Mortality in COPD: causes, risk factors, and prevention. COPD 2010;7:375-82. 
  7. Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645-53. 
  8. White AJ, Gompertz S, Stockley RA. Chronic obstructive pulmonary disease. 6: The aetiology of exacerbations of chronic obstructive pulmonary disease. Thorax 2003;58:73-80. 
  9. Zou Y, Chen X, Liu J, Zhou DB, Kuang X, Xiao J, et al. Serum IL-1β and IL-17 levels in patients with COPD: associations with clinical parameters. Int J Chron Obstruct Pulmon Dis 2017;12:1247-54. 
  10. Miller PG, Qiao D, Rojas-Quintero J, Honigberg MC, Sperling AS, Gibson CJ, et al. Association of clonal hematopoiesis with chronic obstructive pulmonary disease. Blood 2022;139:357-68. 
  11. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Fontana: GOLD; 2023. 
  12. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007;370:786-96. 
  13. Lai Z, Markovets A, Ahdesmaki M, Chapman B, Hofmann O, McEwen R, et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res 2016;44:e108. 
  14. Pei S, Liu T, Ren X, Li W, Chen C, Xie Z. Benchmarking variant callers in next-generation and third-generation sequencing analysis. Brief Bioinform 2021;22:bbaa148. 
  15. Wei Z, Wang W, Hu P, Lyon GJ, Hakonarson H. SNVer: a statistical tool for variant calling in analysis of pooled or individual next-generation sequencing data. Nucleic Acids Res 2011;39:e132. 
  16. Strand M, Khatiwada A, Baraghoshi D, Lynch D, Silverman EK, Bhatt SP, et al. Predicting COPD progression in current and former smokers using a joint model for forced expiratory volume in 1 second and forced expiratory volume in 1 second to forced vital capacity ratio. Chronic Obstr Pulm Dis 2022;9:439-53. 
  17. Zink F, Stacey SN, Norddahl GL, Frigge ML, Magnusson OT, Jonsdottir I, et al. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood 2017;130:742-52. 
  18. Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014;371:2477-87. 
  19. Levin MG, Nakao T, Zekavat SM, Koyama S, Bick AG, Niroula A, et al. Genetics of smoking and risk of clonal hematopoiesis. Sci Rep 2022;12:7248. 
  20. Dawoud AA, Tapper WJ, Cross NC. Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia 2020;34:2660-72. 
  21. Thomsen M, Nordestgaard BG, Vestbo J, Lange P. Characteristics and outcomes of chronic obstructive pulmonary disease in never smokers in Denmark: a prospective population study. Lancet Respir Med 2013;1:543-50. 
  22. Kuhnert S, Mansouri S, Rieger MA, Savai R, Avci E, Diaz-Pina G, et al. Association of clonal hematopoiesis of indeterminate potential with inflammatory gene expression in patients with COPD. Cells 2022;11:2121. 
  23. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847-52. 
  24. Papi A, Vestbo J, Fabbri L, Corradi M, Prunier H, Cohuet G, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet 2018;391:1076-84.