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

• Type of Material: Article
• Authors: MDM Uddin, Broad Institute of Harvard and MIT; Ngoc Quynh H Nguyen, The University of Texas Health Science Center at Houston; Bing Yu, The University of Texas Health Science Center at Houston; Jennifer A Brody, University of Washington; Akhil Pampana, Broad Institute of Harvard and MIT; Tetsushi Nakao, Broad Institute of Harvard and MIT; Myriam Fornage, The University of Texas Health Science Center at Houston; Jan Bressler, The University of Texas Health Science Center at Houston; Nona Sotoodehnia, University of Washington; Joshua S Weinstock, University of Michigan; Michael C Honigberg, Broad Institute of Harvard and MIT; Daniel Nachun, Stanford University; Romit Bhattacharya, Broad Institute of Harvard and MIT; Gabriel K Griffin, Dana-Farber Cancer Institute; Varuna Chander, Baylor College of Medicine; Richard A Gibbs, Baylor College of Medicine; Jerome Rotter, Innovation at Harbor-UCLA Medical Center; Chunyu Liu, Boston University; Andrea A Baccarelli, Columbia University; Daniel Chasman, Harvard Medical School; Eric A Whitsel, University of North Carolina; Douglas P Kiel, Harvard Medical School; Joanne M Murabito, Boston University; Eric Boerwinkle, The University of Texas Health Science Center at Houston; Benjamin L Ebert, Dana-Farber Cancer Institute, Boston; Siddhartha Jaiswal, Stanford University; James S Floyd, University of Washington; Alexander G Bick, Vanderbilt University; Chrsitie M Ballantyne, Baylor College of Medicine; Bruce M Psaty, University of Washington; Pradeep Natarajan, Broad Institute of Harvard and MIT; Karen Conneely, Emory University
• Language: English
• Date: 2022-09-12
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-33093-3
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 5350
• End Page: 5350
• Keywords: Science & Technology - Other Topics; Science & Technology; MICROARRAY; MUTATIONS; INFLAMMASOME; TRANSCRIPTION FACTOR ERG; STEM-CELLS; ASSOCIATION; DNMT3A; HYPERMETHYLATION; METAANALYSIS; GENETIC-LOCI; Multidisciplinary Sciences
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Pathology; Health Sciences, Medicine and Surgery; Environmental Sciences

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.