Association of clonal hematopoiesis with chronic obstructive pulmonary disease
Open accessAbstract
Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, −5.7%; adjusted 95% CI, −8.8% to −2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.
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In a murine emphysema model, recipients of Tet2 knockout bone marrow cells show increased development of disease, even at donor chimerism of only 15% corresponding to a human VAF of about 7.5%.
“the authors reported increased development of the disease in recipients of Tet2 knockout bone marrow cells, even at donor chimerism of only 15% corresponding to a human variant allelic frequency (VAF) of about 7.5% [34].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [34]
The Mouse models methods describe transplanting Tet2-knockout bone marrow, and the Results report enhanced emphysema in mice with approximately 15% Tet2-deficient hematopoietic cells after six months of cigarette-smoke exposure. The cited passages do not state that this corresponds to a human VAF of about 7.5%; that conversion is an inference rather than a reported finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredClinically adverse effects in humans are typically associated with VAFs of 10% or greater.
“Of note, clinically adverse effects in humans have been typically associated with VAFs of 10% or greater [32,34].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [34]
The Results section (page not available) reports that, in an exploratory UK Biobank analysis, CHIP with VAF >10% was associated with increased COPD incidence, whereas CHIP with VAF <10% was not significantly associated. That supports the threshold for this particular outcome, but not the broader claim that clinically adverse effects in humans are typically associated with VAFs of 10% or greater. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCH is associated with chronic obstructive pulmonary disease and other pulmonary disease.
“Various other systemic effects have been described in association with CH, including chronic obstructive pulmonary disease and other pulmonary disease [16,33,34]”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [34]
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Florez, M. A., Tran, B. T., Wathan, T. K., DeGregori, J., Pietras, E. M., & King, K. Y. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.05.006 · Cited by 129 · see citing works
Clonal hematopoiesis and inflammation – the perpetual cycle
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- Authors
- Miller, P. G., Qiao, D., Rojas-Quintero, J., Honigberg, M. C., Sperling, A. S., Gibson, C. J., Bick, A. G., Niroula, A., McConkey, M. E., Sandoval, B., Miller, B. C., Shi, W., Viswanathan, K., Leventhal, M., Werner, L., Moll, M., Cade, B. E., Barr, R. G., Correa, A., Cupples, L. A., Gharib, S. A., Jain, D., Gogarten, S. M., Lange, L. A., London, S. J., Manichaikul, A., O’Connor, G. T., Oelsner, E. C., Redline, S., Rich, S. S., Rotter, J. I., Ramachandran, V., Yu, B., Sholl, L., Neuberg, D., Jaiswal, S., Levy, B. D., Owen, C. A., Natarajan, P., Silverman, E. K., van Galen, P., Tesfaigzi, Y., Cho, M. H., Ebert, B. L., & for the COPDGene Study Investigators, N. H.
- Affiliations
- Broad Institute (US)
- Channing Division of Network Medicine, Department of Medicine, and
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, and
- Vanderbilt University Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Columbia University Irving Medical Center (US)
- University of Mississippi Medical Center (US)
- Boston University (US)
- Computational Medicine Core, Center for Lung Biology, and
- University of Washington (US)
- University of Colorado Anschutz (US)
- National Institutes of Health (US)
- University of Virginia (US)
- University of California, Los Angeles (US)
- Department of Biostatistics, Boston University School of Public Health, Boston, MA;
- The University of Texas Health Science Center at Houston (US)
- Stanford University (US)
- Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA;
- Corresponding author
- Cho, Michael H.
- Ebert, Benjamin L.
- ORCID
- Miller, Peter G.
- Qiao, Dandi
- Rojas-Quintero, Joselyn
- Honigberg, Michael C.
- Sperling, Adam S.
- Gibson, Christopher J.
- Bick, Alexander G.
- Niroula, Abhishek
- McConkey, Marie E.
- Sandoval, Brittany
- Miller, Brian C.
- Shi, Weiwei
- Leventhal, Matthew
- Werner, Lillian
- Moll, Matthew
- Cade, Brian E.
- Barr, R. Graham
- Correa, Adolfo
- Cupples, L. Adrienne
- Gharib, Sina A.
- Jain, Deepti
- Gogarten, Stephanie M.
- Lange, Leslie A.
- London, Stephanie J.
- Manichaikul, Ani
- O’Connor, George T.
- Oelsner, Elizabeth C.
- Redline, Susan
- Rich, Stephen S.
- Rotter, Jerome I.
- Yu, Bing
- Sholl, Lynette
- Neuberg, Donna
- Jaiswal, Siddhartha
- Levy, Bruce D.
- Owen, Caroline A.
- Natarajan, Pradeep
- Silverman, Edwin K.
- van Galen, Peter
- Tesfaigzi, Yohannes
- Cho, Michael H.
- Ebert, Benjamin L.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2022-01-20
- Volume
- 139
- Issue
- 3
- Pages
- 357-368
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC8777202
- OpenAlex
- W3214447846
- Cited by
- 235
- References
- 6
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 66 · 2023: 50 · 2022: 45
- FWCI
- 26.14
- Type
- journal article
- Language
- en
- Update notices
- erratum (2023-02-09)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Blood (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Health and Human Services (75N92019D00031)
- American Society of Hematology
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- Jackson State University
- COPD Foundation (NCT00608764)
- European Hematology Association (TRTH160)
- Sunovion
- Evans Medical Foundation (N01-HC25195)
- Knut och Alice Wallenbergs Stiftelse
- National Institutes of Health (n01hc95164-17-0-1, 1ul1rr033176-01, 75N92019D00031, UL1TR001420, 1r01hl120393-01a1, n01hc95165-34-0-1, n01hc95161-24-0-1, n01hc095169-003, n01hc95166-21-0-1, 5k01hl135405-04, n01hc95162-31-0-1, n01hc95168-27-0-1, n01hc95160-18-0-1, n01hc095167-000, 5r01hl098031-04, HL0-86694, UL1TR001079, n01hc25195-41-0-1, n01hc95163-22-0-1, n01hc95159-40-0-1, UL1TR000040, HL135142, HL007427, HL068111, HL092577, HL089897, N01-HC 25195, HL089856, UL1TR001881, 5r01hl068111-18)
- Genentech
- National Heart, Lung, and Blood Institute (R01HL071205, R03HL154284, N01-HC095169, 75N92020D00001, N01-HC-095165, 75N92020D00006, R01HL082945, R01HL113264, N01 HC095163, R01-HL120393, N01‐HC25195, K01-HL135405, R01HL071259, R01HL148050, 75N92020D00007, R35HL135818, R01HL071251, K01HL129039, 75N92020D00002, N01-HC-095159, N01 HC095168, R01-HL068111, DP2HL157540, N01-HC-095162, U01HL120393, R01HL089856, N01-HC-095161, 75N92020D00005, HL007427, R01HL071051, 75N92019D00031, R01HL071250, 75N92020D00003, N01-HC-025195, HL089897, R01HL087641, HL068111, U01HL089856, N01 HC095167, N01-HC-095160, N01 HC095166, N01 HC095164, U01HL089897, HL092577, R01HL071258, R01 HL098031, R01HL117626, HL089856, NCT00608764, 75N92020D00004, HL086694, R01HL077612, T32HL094301, R01HL092577, T32HL007427, R01HL135142, R01HL086694, R01HL153805)
- National Human Genome Research Institute (U54HG003067, U01HG004402, U54HG003273, U54HG006493)
- NIH Office of the Director (DP5-OD02958, HL007427)
- National Cancer Institute (K08CA252174, R35CA253125, K08CA248960, P01CA108631, P01CA066996, K12CA087723, K08CA263183)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Institute of Environmental Health Sciences (Z01ES043012)
- National Center for Research Resources (UL1-RR-033176)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- clonal hematopoiesis of indeterminate potential, chronic obstructive pulmonary disease, emphysema, TET2, somatic mutations, cigarette smoking, FEV1, COPD severity, hematopoietic cells, inflammation, COPDGene
- MeSH terms
- Exome Sequencing, Clonal Hematopoiesis, Animals, Female, Humans, Male, Middle Aged, Risk Factors, Smoking, Odds Ratio, Pulmonary Disease, Chronic Obstructive, Mice
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