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

TitleClonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.
Publication TypeJournal Article
Year of Publication2022
AuthorsUddin MDMesbah, Nguyen NQuynh H, Yu B, Brody JA, Pampana A, Nakao T, Fornage M, Bressler J, Sotoodehnia N, Weinstock JS, Honigberg MC, Nachun D, Bhattacharya R, Griffin GK, Chander V, Gibbs RA, Rotter JI, Liu C, Baccarelli AA, Chasman DI, Whitsel EA, Kiel DP, Murabito JM, Boerwinkle E, Ebert BL, Jaiswal S, Floyd JS, Bick AG, Ballantyne CM, Psaty BM, Natarajan P, Conneely KN
JournalNat Commun
Volume13
Issue1
Pagination5350
Date Published2022 Sep 12
ISSN2041-1723
KeywordsClonal Hematopoiesis, Coronary Artery Disease, DNA Methylation, Hematopoiesis, Hematopoietic Stem Cells, Humans
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.

DOI10.1038/s41467-022-33093-3
Alternate JournalNat Commun
PubMed ID36097025
PubMed Central IDPMC9468335
Grant ListU34AG051418 / / U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) /