| Title: | Genetic IL-6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis |
| Journal: | Circulation |
| Published: | 11 Nov 2019 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/31707836/ |
| DOI: | https://doi.org/10.1161/circulationaha.119.044362 |
| URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCULATIONAHA.119.044362 |
Publication 4920
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
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.</p>
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; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=0.036).</p>
CONCLUSIONS: CHIP is associated with increased risk of incident CVD. Among carriers of large CHIP clones, genetically reduced IL-6 signaling abrogated this risk.</p>
16 Keywords
- Aged
- Cardiovascular Diseases
- Clonal Evolution
- Female
- Hematopoiesis
- Humans
- Incidence
- Interleukin-6
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Proportional Hazards Models
- Prospective Studies
- Receptors, Interleukin-6
- Risk Factors
- Signal Transduction
9 Authors
- Alexander G Bick
- James P Pirruccello
- Gabriel K Griffin
- Namrata Gupta
- Stacey Gabriel
- Danish Saleheen
- Peter Libby
- Sekar Kathiresan
- Pradeep Natarajan
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
Enabling scientific discoveries that improve human health