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Circulation DOI:10.1161/CIRCULATIONAHA.119.044362

Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis.

Publication TypeJournal Article
Year of Publication2019
AuthorsBick, AG, Pirruccello, JP, Griffin, GK, Gupta, N, Gabriel, S, Saleheen, D, Libby, P, Kathiresan, S, Natarajan, P
Date Published2019 Nov 11

Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells due to acquired leukemic mutations in genes such as or . In humans, CHIP associates with prevalent myocardial infarction. In mice, CHIP accelerates atherosclerosis and increases IL-6/IL-1β expression, raising the hypothesis that IL-6 pathway antagonism in CHIP carriers would decrease cardiovascular disease (CVD) risk. We analyzed exome sequences from 35,416 individuals in the UK Biobank without prevalent CVD, to identify participants with or CHIP. We used the p.Asp358Ala coding mutation as a genetic proxy for IL-6 inhibition. We tested the association of CHIP status with incident CVD events (myocardial infarction, coronary revascularization, stroke, or death), and whether it was modified by p.Asp358Ala. We identified 1,079 (3.0%) individuals with CHIP, including 432 (1.2%) with large clones (allele fraction >10%). During 6.9-year median follow-up, CHIP associated with increased incident CVD event risk (HR=1.27, 95% CI: 1.04-1.56, p=0.019), with greater risk from large CHIP clones (HR=1.59, 95% CI: 1.21-2.09, p<0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (HR=0.46, 95% CI: 0.29-0.73, p<0.001) but not in individuals without CHIP (HR=0.95, 95% CI: 0.89-1.06, p=0.08) (p=0.003). In 9,951 independent participants, the association of CHIP status with myocardial infarction similarly varied by p.Asp358Ala (pinteraction=0.036). CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.


Alternate JournalCirculation
PubMed ID31707836