Open AccessClonal hematopoiesis associated with epigenetic aging and clinical outcomes
Author(s) -
Nachun Daniel,
Lu Ake T.,
Bick Alexander G.,
Natarajan Pradeep,
Weinstock Joshua,
Szeto Mindy D.,
Kathiresan Sekar,
Abecasis Goncalo,
Taylor Kent D.,
Guo Xiuqing,
Tracy Russ,
Durda Peter,
Liu Yongmei,
Johnson Craig,
Rich Stephen S.,
Van Den Berg David,
Laurie Cecilia,
Blackwell Tom,
Papanicolaou George J.,
Correa Adolfo,
Raffield Laura M.,
Johnson Andrew D.,
Murabito Joanne,
Manson JoAnn E.,
Desai Pinkal,
Kooperberg Charles,
Assimes Themistocles L.,
Levy Daniel,
Rotter Jerome I.,
Reiner Alex P.,
Whitsel Eric A.,
Wilson James G.,
Horvath Steve,
Jaiswal Siddhartha
Publication year - 2021
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13366
Subject(s) - epigenetics , biology , dna methylation , genetics , telomere , hazard ratio , oncology , medicine , gene , gene expression , confidence interval
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.