CHIP is associated with cardiovascular disease in the UK Biobank
Vlasschaert, C.; Genovese, G.; Pershad, Y.; Jaiswal, S.; Natarajan, P.; Bick, A. G.
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Clonal hematopoiesis (CH) is a form of age-related somatic mosaicism. CH encompasses both clonal events with recognizable leukemic driver mutations, such as CH of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs), as well as clonal states without clear driver mutations. Stacey et al. identify cases of CH from whole genome sequencing (WGS) data in a subset of 130,709 UK Biobank (UKB) participants and in 45,510 individuals from an Icelandic cohort. They report that CH is not associated with cardiovascular disease (CVD) and posit that the multiple prior CH studies did not fully account for smoking-related confounding. We find that the conclusion reached by Stacey et al. is specific to their particular CH definition which groups well-established and clinically meaningful CH subtypes together despite evidence from multiple previous reports that distinct forms of CH have distinct phenotypic consequences. We show that (1) the CHIP/ CVD association in the UK Biobank is not confounded by smoking and (2) CH subtypes which Stacey et al. have lumped together have heterogenous associations with CVD. We suggest that Stacey et al.s failure to identify an association between CHIP and CVD is perhaps related to methodologic differences compared to prior reports.
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