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.

Clonal hematopoiesis, multi-omics and coronary artery disease

“…Interestingly, individuals with CHIP have greater cardiovascular risk stratification with accelerated methylation aging clocks compared to individuals without. Consistent with murine studies, epigenome-wide association studies show that TET2 CHIP is associated with increased CpG methylation, whereas DNMT3A CHIP is associated with decreased CpG methylation in blood cells 15 . Mendelian randomization analyses indicate that some of the CpG changes may promote CHIP-associated CAD risk.…”

Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease

“…72,73 In the latter study, increased methylation at 3 CpG (cystine-phosphate-guanine) sites (near RGS12, DOCK9, and LRP1) supported potentially new causal mechanisms between TET2 CHIP and CAD using Mendelian randomization procedures. 73 Vitamin C treatment was proposed as a strategy to ameliorate hypermethylation from TET2 loss-of-function mutations. Exogenous vitamin C promotes demethylation in stem cells, particularly in a TET-dependent manner.…”

“…72,73 Mendelian randomization analyses suggest that DNMT3A CHIP-promoted hypomethylation at some sites may promote the development of CAD. 73 More recent single-cell multiomics analysis of individuals with the DNMT3A p.R882 hotspot mutation more specifically characterizes methylation changes attributed to this mutation. 81 JAK2 P.V617F JAK2 p.V617F is identified in the vast majority of patients with myeloproliferative neoplasms .…”

“…80 Although DNMT3A CHIP is associated with widespread hypomethylation, it leads to a similar phenotype of hematopoietic stem cell self-renewal and proliferation as TET2 CHIP. 72,73 Mendelian randomization analyses suggest that DNMT3A CHIP-promoted hypomethylation at some sites may promote the development of CAD. 73 More recent single-cell multiomics analysis of individuals with the DNMT3A p.R882 hotspot mutation more specifically characterizes methylation changes attributed to this mutation.…”

Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment

“…In CHIP, hematopoietic stem cells with somatic mutations modulate hematopoietic lineage potential by a mechanism of clonal expansion. CHIP is associated with an increased risk for hematologic malignancies and cardiovascular diseases [ 237 – 248 ]. It also associates with adverse outcomes in patients with other advanced malignancies [ 249 ].…”