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Risk Factors for Clonal Hematopoiesis of Indeterminate Potential and Mosaic Chromosomal Alterations

  • Yasminka A. Jakubek
    Affiliations
    Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY
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  • Alexander P. Reiner
    Correspondence
    Corresponding author: Alexander P. Reiner, Fred Hutchinson Cancer Research Center, Box 358080, WHI Clinical Coordinating Center / Public Health Sciences, M3-A4, Seattle, WA, 98109
    Affiliations
    Division of Public Health Sciences, Fred Hutchinson Center Research Center, Seattle, WA

    Department of Epidemiology, University of Washington, Seattle, WA
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  • Michael C. Honigberg
    Affiliations
    Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA

    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
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Published:November 19, 2022DOI:https://doi.org/10.1016/j.trsl.2022.11.009

      Abstract

      Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) of the autosomes, X, and Y chromosomes are aging-related somatic mutations detectable in peripheral blood. The presence of these acquired mutations predisposes otherwise healthy adults to increased risk of several chronic aging-related conditions including hematologic cancers, atherosclerotic cardiovascular diseases, other inflammatory conditions, and mortality. While the public health impact and disease associations of these blood-derived somatic mutations continue to expand, the inherited, behavioral/lifestyle, environmental risk factors and comorbid conditions that influence their occurrence and progression have been less well characterized. Age is the strongest risk factor for all types of CHIP and mCAs. CHIP and mCAs are generally more common in individuals of European than non-European ancestry. Evidence for a genetic predisposition has been strongest for mosaic loss of Y chromosome in men. Genome-wide association studies have recently begun to identify common and rare germline genetic variants associated with CHIP and mCAs. These loci include genes involving cell cycle regulation, cell proliferation/survival, hematopoietic progenitor cell regulation, DNA damage repair, and telomere maintenance. Some loci, such as TERT, ATM, TP53, CHEK2, and TCL1A, have overlapping associations with different types of CHIP, mCAs, and cancer predisposition. Various environmental or co-morbid contexts associated with presence or expansion of specific CHIP or mCA mutations are beginning to be elucidated, such as cigarette smoking, diet, cancer chemotherapy, particulate matter, and premature menopause. Further characterization of the germline genetic and environmental correlates of CHIP/mCAs may inform our ability to modify their progression and ultimately reduce the risk and burden of chronic diseases associated with these clonal somatic phenomena.

      Keywords

      Abbreviations:

      AML (acute myeloid leukemia), ARIC (Atherosclerosis Risk in Communities), CAD (coronary artery disease), CHIP (Clonal hematopoiesis of indeterminate potential), CLL (chronic lymphocytic leukemia), CVD (cardiovascular diseases), GWAS (genome-wide association analyses), HIV (Human immunodeficiency virus), LDL-C (low-density lipoprotein cholesterol), pLOF (putative loss-of-function), MAF (minor allele frequency), MDS (myelodysplastic syndromes), MPN (myeloproliferative neoplasms), MR (Mendelian randomization), PheWAS (phenome-wide association studies), TOPMed (Trans-Omics for Precision Medicine), UKB (UK Biobank), VAF (variant allele fraction), cn-LOH (copy number neutral loss of heterozygosity), eQTL (expression quantitative trait locus), mCA-auto (mosaic chromosomal alterations), mLOX (mosaic loss of chromosome X), mLOY (mosaic loss of chromosome Y)
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