NEW YORK – A handful of germline gene variants contribute to the risk of developing aging-related clonal hematopoiesis, a new study has found.
As people age, they can acquire somatic mutations that lead to clonal expansion within their population of regenerating hematopoietic stem cells, which in turn can lead to hematological cancer and coronary heart disease. To find germline drivers of this condition, called clonal hematopoiesis of indeterminate potential (CHIP), a team led by Broad Institute researchers examined the genomes of thousands of individuals with and without CHIP.
As the researchers reported on Wednesday in Nature, they identified three germline genetic loci associated with CHIP, including one in the TET2 gene that appears to be specific to individuals of African ancestry. They further traced that locus to a likely causal variant that affects a TET2 enhancer to lead to an increase in the self-renewal of hematopoietic stem cells.
"Overall, we observe that germline genetic variation shapes hematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal hematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues," co-senior authors Sekar Kathiresan and Pradeep Natarajan, both of the Broad, and their colleagues wrote in their paper.
The researchers used a somatic variant caller to identify individuals from the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) program cohort with CHIP. They relied on a pre-selected list of leukemogenic driver mutations to identify these CHIP carriers. In all, they uncovered 4,938 CHIP mutations in 4,229 individuals from the TOPMed cohort of 97,000 participants. The researchers noted that the prevalence of CHIP increased with the age at which the blood samples were taken from participants, as well as with a history of smoking.
About three-quarters of individuals with CHIP had mutations in just three genes: DNMT3A, TET2, and ASXL1. Some CHIP characteristics varied by driver gene mutation. For instance, JAK2 CHIP mutation carriers were generally younger than other carriers, and TET2 CHIP carriers tended to have increased IL-1β levels, while JAK2 and SF3B1 carriers had increased circulating IL-18.
Within a subset of this cohort, the researchers conducted a single-variant genome-wide association analysis to uncover germline variants linked to CHIP. Through their analysis and subsequent replication, they uncovered one variant in TERT that was associated with a 1.3-fold increased risk of developing CHIP, as well as a variant near both KPNA4 and TRIM59 that was associated with a 1.16-fold increased risk and a variant near TET2 that was associated with a 2.4-fold increased risk of developing CHIP.
The variant near TET2, the researchers noted, was specific to individuals with African ancestry, and had not previously been linked to disease, possibly due to the underrepresentation of individuals of African ancestry in genetic association studies.
This variant predisposes individuals to developing CHIP driven by a number of somatic mutations, suggesting the variant doesn't specifically predispose individuals to TET2-specific CHIP.
The researchers homed in on a set of about two dozen likely causal variants, which they hypothesized affects a TET2 enhancer in hematopoietic stem cells. In a series of assays, they found that individuals with this variant had decreased TET2 expression and that the reduction of TET2 activity was linked to increased self-renewal and proliferation of hematopoietic stem cells. This, the researchers wrote, shows that "at this locus, both germline noncoding and somatic coding variation converge to affect TET2 and influence the development of CHIP."
The researchers added that their work further emphasizes the need to study the genomes of people with diverse ancestral backgrounds. They suggested that additional studies of diverse populations will likely uncover other important biological pathways.