Journal
AGING CELL
Volume 20, Issue 6, Pages -Publisher
WILEY
DOI: 10.1111/acel.13366
Keywords
clonal hematopoiesis; epigenomics; heart disease
Categories
Funding
- National Heart, Lung, and Blood Institute (NHLBI)
- Broad Institute of MIT and Harvard [HHSN268201500014C, 3R01HL092577-06S1, 3U54HG003067-12S2]
- University of Washington Northwest Genomics Center [HHSN268201100037C]
- TOPMed Informatics Research Center [3R01HL-117626-02S1, HHSN268201800002I]
- TOPMed Data Coordinating Center [3R01HL-120393-02S1, HHSN268201800001I]
- Jackson State University [HHSN268201800013I]
- Tougaloo College [HHSN268201800014I]
- Mississippi State Department of Health [HHSN268201800015I]
- University of Mississippi Medical Center [HHSN268201800010I, HHSN268201800011I, HHSN268201800012I]
- National Institute for Minority Health and Health Disparities (NIMHD)
- National Center for Advancing Translational Sciences, CTSI grant [UL1TR001881]
- National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
- National Center for Research Resources [UL1RR033176]
- Women's Health Initiative [phs001237]
- National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, HHSN268201600004C]
- Burroughs Wellcome Foundation Career Award for Medical Scientists
- Foundation Leducq
- Ludwig Center for Cancer Stem Cell Research
- American Society of Hematology Scholar Award
- NIH Director's New Innovator Award [DP2-HL157540]
- Burroughs Wellcome Foundation
- NIH Director's Early Independence Award [DP5-OD029586]
- [75N92020D00001]
- [HHSN268201500003I]
- [N01-HC-95159]
- [75N92020D00005]
- [N01-HC-95160]
- [75N92020D00002]
- [N01-HC-95161]
- [75N92020D00003]
- [N01-HC-95162]
- [75N92020D00006]
- [UL1-TR-000040]
- [UL1-TR-001079]
- [UL1-TR-001420]
- [R01HL071051]
- [R01HL071205]
- [R01HL071250]
- [R01HL071251]
- [R01HL071258]
- [R01HL071259]
- [1T32AG047126-01]
- [N01-HC-95163]
- [75N92020D00004]
- [N01-HC-95164]
- [75N92020D00 007]
- [N01-HC-95165]
- [N01-HC-95166]
- [N01-HC-95167]
- [N01-HC-95168]
- [N01-HC-95169]
Ask authors/readers for more resources
Clonal hematopoiesis of indeterminate potential (CHIP) is strongly associated with epigenetic age acceleration, with carriers of multiple gene mutations showing the largest increase in age acceleration. About 40% of CHIP carriers have acceleration >0 in both clocks, and this subgroup is at higher risk for adverse outcomes, making them potential targets for clinical interventions.
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 x 10(-7)) to 3.08 years (EEAA, p < 3.7 x 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 similar to 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 x 10(-8)) and coronary heart disease (CHD) (hazard ratio 3.24, p < 9.3 x 10(-6)) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other similar to 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.
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