Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis.

Circulation
Authors
Abstract

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable 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.

METHODS: 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.

RESULTS: We identified 1079 (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 (hazard ratio, 1.27 [95% CI, 1.04-1.56], =0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21-2.09],

CONCLUSIONS: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.

Year of Publication
2020
Journal
Circulation
Volume
141
Issue
2
Pages
124-131
Date Published
2020 Jan 14
ISSN
1524-4539
DOI
10.1161/CIRCULATIONAHA.119.044362
PubMed ID
31707836
PubMed Central ID
PMC7008855
Links
Grant list
MC_QA137853 / MRC_ / Medical Research Council / United Kingdom
R01 HL148565 / HL / NHLBI NIH HHS / United States
R01 HL134892 / HL / NHLBI NIH HHS / United States
R01 HL080472 / HL / NHLBI NIH HHS / United States
R01 HL142711 / HL / NHLBI NIH HHS / United States
MC_PC_17228 / MRC_ / Medical Research Council / United Kingdom
R01 HL148050 / HL / NHLBI NIH HHS / United States