Clonal hematopoiesis: Mutation-specific adaptation to environmental change.

Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays' high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual.We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women's Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy.Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale. 

https://immunityageing.biomedcentral.com/counter/pdf/10.1186/s12979-022-00278-9

Longitudinal profiling of clonal hematopoiesis provides insight into clonal dynamics

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. 

/pdf/clonal-hematopoiesis-of-indeterminate-potential-dna-1q4f2os0.pdf

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

Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging hematopoietic stem cells (HSCs) acquire somatic mutations which confer a clonal survival advantage in their progeny. These cells confer increased leukemogenic risk but confer a greater absolute risk of cardiovascular disease—which appears to be mediated through altered inflammatory pathways. Here we review the evidence the risk of cardiovascular disease conferred by CHIP. We also review the evidence regarding risk factors associated with CHIP. The most recent evidence suggests that CHIP is associated with increased cardiovascular risk beyond atherosclerosis, which has been established in multiple studies, but also in heart failure and aortic valve stenosis. Additionally, the list of conditions associated with CHIP continues to grow including germline genetics, smoking, cancer therapies, radiation exposure, premature menopause, and unhealthy diet. CHIP is a cardiovascular risk factor of increasingly recognized importance, and new data continues to emerge about the risks it confers, which will need more prospective validation. Although risk factors for CHIP are being identified, relatively little is known about the mechanisms by which CHIP develops, which requires further study.

Clonal Hematopoiesis of Indeterminate Potential: an Expanding Genetic Cause of Cardiovascular Disease.

Aging is associated with clonal hematopoiesis (CH) caused by somatic mutations in blood cell progenitors. Mutations with [≥]2% variant allele frequency (VAF), known as clonal hematopoiesis of indeterminate potential (CHIP) mutations, have been linked to risk of hematological malignancies and cardiovascular disease. Using an ultrasensitive single-molecule molecular inversion probe (smMIP) sequencing assay, we identified clonal hematopoiesis driver mutations (CHDMs) in a set of established CH driver genes in individuals with obesity from the Swedish Obese Subjects study. In cross-sectional setting, with samples from 1050 individuals, we identified 273 candidate CHDMs in 216 individuals, with a VAF ranging from 0.01% to 31.15% and with clone sizes and prevalence increasing with age. Longitudinal analysis over 20 years in 40 individuals showed that small clones may grow over time and become CHIP. Greater speed of clone growth was associated with insulin resistance (R=0.04, P=0.025) and low circulating levels of high-density lipoprotein-cholesterol (R=-0.68, P=1.74E-05), suggesting that dysfunctional metabolism may accelerate expansion of CH.

/pdf/clone-expansion-of-mutation-driven-clonal-hematopoiesis-is-2yf49zzh85.pdf

Kristensson

Papers

Clone expansion of mutation-driven clonal hematopoiesis is associated with aging and metabolic dysfunction in individuals with obesity