Association of clonal hematopoiesis with chronic obstructive pulmonary disease

Abstract

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 with COPD remains unclear. We analyzed whole-genome and exome sequencing data to detect CHIP in 48,835 subjects, of whom 8,444 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 COPDGene, individuals with CHIP had a risk of moderate-to-severe and severe or very severe COPD 1.6 and 2.2 times greater than non-carriers, respectively (adjusted 95% confidence intervals [CI], 1.1 to 2.2 and 1.5 to 3.2). These findings were consistent observed in three additional cohorts and meta-analyses of all subjects. CHIP was also associated with decreased FEV1% predicted in COPDGene (mean between group difference -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 (OR 1.03 per ten pack-years, 95% CI 1.01-1.05) in the meta-analysis of all subjects. Inactivation of Tet2 in mouse hematopoietic cells exacerbated emphysema development and inflammation in cigarette smoke exposure models. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure.

Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

“…2a). In contrast, presence of TET2 CHIP was associated with decreasing DNAm at 0.23% (1,092) of sites and increasing DNAm at 2.24% (10,713) of sites (Fig. 2d, Supplementary Fig.…”

“…The prevalence of CHIP detectable through next-generation sequencing of blood DNA is up to 10% of adults >70 years and nearly 20% of adults >90 years [2][3][4] . CHIP is associated with increased risk for hematological cancers 2 , coronary artery disease (CAD) 4,5 , congestive heart failure 6 , stroke 7 , chronic obstructive pulmonary disease [8][9][10] , osteoporosis 11 , and all-cause mortality 2,3 . The genes most commonly mutated in clonal hematopoiesis are DNMT3A and TET2 4 , and in general CHIP mutations are overrepresented in genes regulating HSC proliferation and tumor suppression.…”

Clonal hematopoiesis is not prevalent in Hutchinson-Gilford progeria syndrome

“…Furthermore, CHIP has also been associated with an adverse clinical progression of heart failure, a leading cause of hospitalization for elderly individuals [7,9]. Beyond heart disease, some CHIP mutations have been suggested to contribute to the development and progression of a variety of conditions prevalent in the elderly, such as osteoporosis, chronic obstructive pulmonary disease, chronic kidney disease, or insulin resistance [11][12][13][14]. However, despite the accumulating evidence supporting the clinical relevance of CHIP in normal aging, its potential contribution to the pathophysiology of accelerated aging syndromes remains unexplored.…”

Combination strategies to promote sensitivity to cytarabine-induced replication stress in acute myeloid leukemia with and without DNMT3A mutations

“…Similar to other tissues such as esophagus and skin (56-60), age-related clonal expansion of HSCs is a common phenomenon, termed clonal hematopoiesis (CH) (61). While emergence of small clones defined by variant allele frequency (VAF) <2% without overt hematologic abnormalities is ubiquitous, presence of larger CH clones (VAF >10%) is associated with increased risk of blood malignancies (62)(63)(64)(65)(66)(67)(68) and other adverse outcomes ranging from atherosclerosis to cancer to chronic kidney disease (69)(70)(71)(72).…”