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Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p < 8.6 × 10^-7 ) to 3.08 years (EEAA, p < 3.7 × 10^-18 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p < 4.1 × 10^-8 ) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 × 10^-6 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.

SUBMITTER: Nachun D

PROVIDER: S-EPMC8208788 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

Nachun Daniel D Lu Ake T AT Bick Alexander G AG Natarajan Pradeep P Weinstock Joshua J Szeto Mindy D MD Kathiresan Sekar S Abecasis Goncalo G Taylor Kent D KD Guo Xiuqing X Tracy Russ R Durda Peter P Liu Yongmei Y Johnson Craig C Rich Stephen S SS Van Den Berg David D Laurie Cecilia C Blackwell Tom T Papanicolaou George J GJ Correa Adolfo A Raffield Laura M LM Johnson Andrew D AD Murabito Joanne J Manson JoAnn E JE Desai Pinkal P Kooperberg Charles C Assimes Themistocles L TL Levy Daniel D Rotter Jerome I JI Reiner Alex P AP Whitsel Eric A EA Wilson James G JG Horvath Steve S Jaiswal Siddhartha S

Aging cell 20210529 6

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing ...[more]

PMID: 34050697

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Project description:Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.

Dataset Information

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

Publications

Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.

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