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Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis
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 DNMT3A or TET2 . 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 DNMT3A or TET2 CHIP. We used the IL6R 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 IL6R 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], P =0.019), with greater risk from large CHIP clones (hazard ratio, 1.59 [95% CI, 1.21–2.09], P <0.001). IL6R p.Asp358Ala attenuated CVD event risk among participants with large CHIP clones (hazard ratio, 0.46 [95% CI, 0.29–0.73], P <0.001) but not in individuals without CHIP (hazard ratio, 0.95 [95% CI, 0.89–1.01], P =0.08; P interaction =0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala ( P interaction =0.036). Conclusions: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.
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“A number of recent large cohort studies have associated clonal hematopoiesis with an increase in all-cause mortality (9-13).”
From Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction (2020) · cites this paper as [9]
In the citing paper
“evidence suggests that these cytokines causally contribute to cardiovascular pathologies (9, 40).”
From Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction (2020) · cites this paper as [9]
In the citing paper
“multiple studies indicate that the mutant HSPCs give rise to progeny blood cells with altered immune properties (e.g., overactivation of IL-1 β /IL-6 signaling) that appear to be causative in the disease process (3, 5, 9, 40).”
From Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction (2020) · cites this paper as [9]
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“This protective association was detected primarily in TET2 and DNMT3A CH22.”
From Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis (2023) · cites this paper as [22]
In the citing paper
“The role of IL-6 signaling in CVD in CH is supported by a study that showed that IL-6RD358A attenuated CVD event risk among participants with large CH clones but not in individuals without CH22.”
From Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis (2023) · cites this paper as [22]
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Metadata
- Authors
- Bick, A. G., Pirruccello, J. P., Griffin, G. K., Gupta, N., Gabriel, S., Saleheen, D., Libby, P., Kathiresan, S., & Natarajan, P.
- Venue
- Circulation
- Published
- 2020-01-14
- Volume
- 141
- Issue
- 2
- Pages
- 124-131
- ISSN
- 0009-7322
- 1524-4539
- PMC
- PMC7008855
- Cited by
- 433
- References
- 15
- Language
- en
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