Inherited Causes of Clonal Hematopoiesis of Indeterminate Potential in TOPMed Whole Genomes

Abstract

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown. 1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence 2-4 and coronary heart disease prevalence. 5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed 'Clonal Hematopoiesis of Indeterminate Potential' (CHIP). 6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

The role of clonal haematopoiesis in cardiovascular diseases: epidemiology and experimental studies

“…Notably, this association was only made with TET2-mediated clonal haematopoiesis, but not with clonal haematopoiesis derived from other known driver genes. This finding appears to dovetail with a recent study reporting that TET2-mediated clonal haematopoiesis, but not by mutations in other driver genes, leads to a detectable elevation in circulating IL-1b levels in the TOPMed cohort [30]. Thus, TET2 appears to uniquely impact the IL-1b signalling pathway.…”

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

“…As these clones expand, they increasingly give rise to progeny blood cells that harbor the mutation. Although clonal hematopoiesis generally does not lead to changes in total blood cell numbers, the leukocytes derived from these mutant clones can exhibit altered inflammatory properties (3)(4)(5)(6)(7)(8)(9).…”

Genetic predisposition to myeloproliferative neoplasms implicates hematopoietic stem cell biology

“…Interestingly, we also noted a suggestive genetic correlation between MPN risk variants and those predisposing to clonal hematopoiesis described in a companion manuscript (rg = 0.39, s.e.m. = 0.21, p = 0.07) 21 , suggesting that these loci may not only promote risk for overt MPNs, but also somatic mutation acquisition in HSCs via a similar mechanism. All of these in vivo phenotypic assessments collectively support a role for modulation of HSC function by MPN risk variants.…”