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Clonal Hematopoiesis Linked to Common, Rare Genetic Variants

NEW YORK – A team of researchers at Regeneron Pharmaceuticals has profiled common and rare variants corresponding with different forms of clonal hematopoiesis of indeterminate potential (CHIP), while pointing to potential relationships between CHIP and a range of other traits and conditions.

"[W]e identify many novel common and rare variant associations with CHIP and other clonal hematopoiesis phenotypes, which help to set the stage for future functional, mechanistic, and therapeutic studies," corresponding author Eric Jorgenson, a researcher with the Regeneron Genetics Center, and his colleagues wrote. "On the whole, our analyses emphasize that CHIP is really a composite of somatic mutation-driven subtypes, with shared genetic etiology and distinct risk profiles."

For a paper appearing in Nature on Wednesday, the researchers focused on 40,208 individuals with CHIP, found by profiling exome sequences for nearly 628,400 individuals enrolled in the UK Biobank project or the Geisinger Health System's (GHS) MyCode Community Health Initiative.

"Identifying individuals with CHIP, which is defined by somatic protein-altering mutations in genes that are recurrently mutated in clonal hematopoiesis, requires sequencing of blood," the authors explained. "Once a clone has expanded sufficiently, the somatic variants from this clone can be captured along with germline variants by exome sequencing."

The team began by using a genome-wide association approach with exome-derived data informed by array-based genotypes to search for common variants with ties to CHIP in 25,657 cases and nearly 342,900 controls, highlighting 57 variants at two dozen CHIP-linked loci that were subsequently validated in another 9,523 CHIP cases and more than 105,500 controls. All but three of the risk loci had not been linked to CHIP in the past, and at least one of these loci — a LY75 gene region coding for a lymphocytic antigen — contained missense alterations that appeared to protect against CHIP.

On the rare variant side, the researchers performed an exome-wide association study using data for more than 27,300 UK Biobank participants and 12,877 individuals from the GHS study who had CHIP-related somatic mutations in genes such as JAK2, IDH2, SRSF2, or DNMT3A.

Although they tracked down just one rare germline variant with significant ties to CHIP, found in the CHEK2 gene, their gene burden analyses revealed an overrepresentation of rare variants in the ATM and CHEK2 genes. In the UK Biobank participants, but not the GHS participants, rare CHIP-related variants were enriched in CTC1, a gene contributing to telomere maintenance and DNA replication.

Along with analyses setting the CHIP-associated variants alongside those implicated in more widely studied forms of clonal hematopoiesis marked by mosaic chromosomal changes, mosaic X or Y sex chromosome loss, or telomere length shifts, the investigators focused on gene mutations distinguishing different CHIP phenotypes.

In CHIP cases marked by DNMT3A mutations, for example, they tracked down half a dozen subtype-specific loci not found in the broader CHIP association analyses. Still other sites seemed to coincide with lower-than-usual risk of DNMT3A-mutated CHIP.

Confirming past results, the researchers found that CHIP was more common in older individuals and in those with a history of smoking. CHIP-related somatic mutations also turned up more often in female UK Biobank participants — an effect that was not found in the GHS study.

The team subsequently turned to phenome-wide association and Mendelian randomization analyses to explore potential ties between CHIP and more than 5,000 other traits or conditions profiled for the UK Biobank project. These uncovered relationships between CHIP and everything from heart disease, blood traits, COVID-19 severity, or infection risk to the risk of solid cancers such as lung and non-melanoma skin cancer.

"Serial sampling would enable the evaluation of changes to CHIP clones over time, and future studies that focus on such serial analysis at large scale will be able to better estimate CHIP subtype-specific clonal changes and clinical risk," the authors noted. "Such increased data assets would also likely facilitate the identification of additional genes that show recurrent mutation during clonal hematopoiesis, as well as how such mutations relate to one another."