Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan 14;141(2):124-131.
doi: 10.1161/CIRCULATIONAHA.119.044362. Epub 2019 Nov 11.

Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis

Alexander G Bick  1   2   3   4 , James P Pirruccello  1   2   3   4 , Gabriel K Griffin  5   4   6 , Namrata Gupta  4 , Stacey Gabriel  4 , Danish Saleheen  7   8 , Peter Libby  9 , Sekar Kathiresan  2   3   4   10 , Pradeep Natarajan  1   2   3   4
Affiliations

Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis

Alexander G Bick et al. Circulation. .

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; Pinteraction=0.003). In 9951 independent participants, the association of CHIP status with myocardial infarction similarly varied by IL6R p.Asp358Ala (Pinteraction=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.

Keywords: cardiovascular disease; exome; hematopoiesis; interleukin-6.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

Figure 1.
Figure 1.. CVD Event Incidence stratified by CHIP carrier status and clone size.
Panel A shows the comparison of time to the primary CVD event outcome of myocardial infarction, coronary artery disease or revascularization, stroke, or death between all CHIP carriers and non-carriers of CHIP. Panel B shows that carriers of large CHIP clones (VAF > 10%) had an increased risk of the primary outcome, while those with small CHIP clones (VAF < 10%) did not have significantly increased risk. VAF = variant allele fraction.
Figure 1.
Figure 1.. CVD Event Incidence stratified by CHIP carrier status and clone size.
Panel A shows the comparison of time to the primary CVD event outcome of myocardial infarction, coronary artery disease or revascularization, stroke, or death between all CHIP carriers and non-carriers of CHIP. Panel B shows that carriers of large CHIP clones (VAF > 10%) had an increased risk of the primary outcome, while those with small CHIP clones (VAF < 10%) did not have significantly increased risk. VAF = variant allele fraction.
Figure 2:
Figure 2:. CVD Event Incidence stratified by CHIP carrier status and genetically determined impairment in IL-6 signaling.
Panel A. Comparison of time to the primary outcome of myocardial infarction, coronary artery disease or revascularization, stroke, or death stratified by IL6R p.Asp358Ala carrier status in (left panel) individuals without CHIP or (right panel) carriers of large CHIP clones (VAF > 10%). Panel B. Among those with large CHIP clones, but not those without CHIP, the presence of IL6R p.Asp358Ala variants conferred a reduced risk of incidence of the primary outcome (pinteraction=0.003).
Figure 2:
Figure 2:. CVD Event Incidence stratified by CHIP carrier status and genetically determined impairment in IL-6 signaling.
Panel A. Comparison of time to the primary outcome of myocardial infarction, coronary artery disease or revascularization, stroke, or death stratified by IL6R p.Asp358Ala carrier status in (left panel) individuals without CHIP or (right panel) carriers of large CHIP clones (VAF > 10%). Panel B. Among those with large CHIP clones, but not those without CHIP, the presence of IL6R p.Asp358Ala variants conferred a reduced risk of incidence of the primary outcome (pinteraction=0.003).
See this image and copyright information in PMC

References

    1. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16. - PMC - PubMed
    1. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. N Engl J Med. 2014; 371:2488–98. - PMC - PubMed
    1. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, Ozenberger BA, Welch JS, Link DC et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014; 20:1472–8. - PMC - PubMed
    1. Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, Purcell SM, Svantesson O, Landén M, et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. New England Journal of Medicine 2014;371:2477–87. - PMC - PubMed
    1. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR, Majeti R. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med. 2012;4:149. - PMC - PubMed

Publication types