Interleukin-6 Receptor Polymorphism Attenuates Clonal Hematopoiesis-Mediated Coronary Artery Disease Risk Among 451 180 Individuals in the UK Biobank

Clonal hematopoiesis of indeterminate potential (CHIP) is a prevalent age-related condition wherein hematopoietic stem cells acquire a pathogenic mutation in a blood cancer driver gene (most commonly DNMT3A or TET2) resulting in a clonal expansion.CHIP is associated with incident coronary artery disease (CAD) in large observational cohorts. 1 Mouse models suggest that IL-1β/IL-6 signaling mediates atherosclerosis in CHIP. 1 A retrospective analysis of CANTOS found that treatment with anti-IL1β antibody canakinumab was associated with lower risk of secondary cardiovascular events in individuals with TET2 CHIP but not DNMT3A CHIP. 2 Additionally, we previously reported that individuals with CHIP who were carriers of a common inherited genetic variant associated with dampened IL-6 signaling (IL6R p.Asp358Ala, rs2228145-C) -a genetic proxy of IL-6 receptor blockade -had a lower risk of incident cardiovascular events in the initial 50,000-person exome sequencing release of the UK Biobank available in 2019.3 More recently, the complete 450,000-person UK Biobank exome dataset has been made available.A preliminary analysis of this dataset by Kessler et al. showed a small effect size for CHIP and CAD risk, and failed to show a protective effect for rs2228145-C 4 , however the authors employed a relaxed genetic variant filtering criteria for CHIP, increasing the likelihood of false positive CHIP calls such as sequencing artifacts and germline variants.