Dataset Information

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-1? 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.

SUBMITTER: Bick AG

PROVIDER: S-EPMC7008855 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Bick Alexander G AG Pirruccello James P JP Griffin Gabriel K GK Gupta Namrata N Gabriel Stacey S Saleheen Danish D Libby Peter P Kathiresan Sekar S Natarajan Pradeep P

Circulation 20191111 2

<h4>Background</h4>Clonal hematopoiesis of indeterminate potential (CHIP) refers to clonal expansion of hematopoietic stem cells attributable to acquired leukemic mutations in genes such as <i>DNMT3A</i> or <i>TET2</i>. 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.<h4>Methods</h4>We ...[more]

PMID: 31707836

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Project description:BackgroundClonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.MethodsWe used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.ResultsIn nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.ConclusionsThe presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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