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New Clonal Hematopoiesis Genetic Risk Loci Identified in UK Biobank Study

NEW YORK — Researchers have uncovered 10 novel germline genetic loci associated with clonal hematopoiesis, an aging-linked condition associated with an increased risk of cancer and other conditions.

Efforts to determine what causes clonal hematopoiesis (CH), the clonal expansion of blood stem cells with somatic driver mutations, and what its effects are have been hampered by its tight association with aging. Using data on more than 200,000 UK Biobank participants, a UK-based team of researchers has now conducted genome-wide analyses to uncover loci associated with clonal hematopoiesis, including those linked to certain clonal hematopoiesis subtypes. In particular, they found variants in two genes, TCL1A and CD164, that had opposing associations in two CH subtypes.

"Collectively, our findings substantially illuminate the landscape of inherited susceptibility to CH and provide insights into the causes and consequences of CH with implications for human health and aging," senior author George Vassiliou from the University of Cambridge and his colleagues wrote in their paper, which appeared Thursday in Nature Genetics.

For their study, the researchers filtered blood whole-exome sequencing data from 200,453 UKB participants for somatic mutations in 43 CH-related genes to uncover known driver variants. In all, they found 11,697 mutations in 10,924 participants, a CH prevalence of nearly 5.5 percent.

Some driver mutations were more likely to emerge at different ages, the researchers noted. For example, mutations in DNMT3A arose earlier than those in SF3B1 and SRSF2.

By also conducting a genome-wide association study of 10,203 individuals with CH and 173,918 without, the researchers searched for germline genetic variants that might affect the development of CH. They identified seven independent CH risk loci that reached genome-wide significance, including three previously reported ones. Following additional analyses, the researchers identified a total of 10 new germline loci associated with CH risk.

They also stratified their CH population to conduct additional GWAS focused on four CH traits: DNMT3A-driven CH, TET2-driven CH, and CH marked by small or large clone sizes. They found eight loci linked to DNMT3A-mutant CH risk and three with TET2-mutant CH risk. Meanwhile, loci at 5p15.33-TERT and 3q25.33-SMC4 were associated with large-clone CH while 5p15.33-TERT and 6q21-CD164 were associated with small-clone CH.

Interestingly, the researchers noted that a signal at 14q32.13-TCL1A that was associated with DNMT3A-mutant CH has the opposite effect for TET2-CH, as did another signal at 6q21-CD164. This finding, they added, is "tantalizing" because the two CH subtypes develop at different ages, with TET2-CH being more common among people over the age of 80, and suggests the loci may have key roles in CH development.

The loci discovered in the study implicated potential new CH susceptibility genes, including CD164, ATM, and SETBP1. Functional analyses further prioritized targets in PARP1 and TERT, which the researchers noted could be druggable.

They also conducted Mendelian randomization (MR) analyses to examine risk factors for CH and its ties to other traits. Genetically predicted smoking initiation and longer leukocyte telomere length were associated with CH risk, while genetically predicted higher body mass index was linked to an increased risk of large-clone CH. They additionally found genetic links between CH risk and myeloproliferative neoplasms, as well as lung, prostate, ovarian, and other cancers. An MR-PheWas additionally noted a link between genetic liability of CH with blood cell traits and hematopoietic cancers.

"Our study reveals multiple new germline loci associated with CH, including several that interact with specific CH subtypes; uncovers causal links between CH and diverse pathological states across organ systems; and provides evidence for causal associations between smoking and telomere length and CH risk, amongst a series of insights," Vassiliou and colleagues wrote.