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


ABSTRACT: Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.

SUBMITTER: Uddin MDM 

PROVIDER: S-EPMC9468335 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Uddin M D Mesbah MDM   Nguyen Ngoc Quynh H NQH   Yu Bing B   Brody Jennifer A JA   Pampana Akhil A   Nakao Tetsushi T   Fornage Myriam M   Bressler Jan J   Sotoodehnia Nona N   Weinstock Joshua S JS   Honigberg Michael C MC   Nachun Daniel D   Bhattacharya Romit R   Griffin Gabriel K GK   Chander Varuna V   Gibbs Richard A RA   Rotter Jerome I JI   Liu Chunyu C   Baccarelli Andrea A AA   Chasman Daniel I DI   Whitsel Eric A EA   Kiel Douglas P DP   Murabito Joanne M JM   Boerwinkle Eric E   Ebert Benjamin L BL   Jaiswal Siddhartha S   Floyd James S JS   Bick Alexander G AG   Ballantyne Christie M CM   Psaty Bruce M BM   Natarajan Pradeep P   Conneely Karen N KN  

Nature communications 20220912 1


Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association s  ...[more]

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