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Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease

Gumuser, Esra D. ; Schuermans, Art ; Cho, So Mi Jemma ; Sporn, Zachary A. ; Uddin, Md Mesbah ; Paruchuri, Kaavya ; Nakao, Tetsushi ; Yu, Zhi ; Haidermota, Sara and Hornsby, Whitney , et al. (2023) In Journal of the American College of Cardiology 81(20). p.1996-2009
Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. Objectives: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. Methods: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%),... (More)

Background: Clonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. Objectives: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. Methods: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. Results: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P < 0.001) and 1.34 (95% CI: 1.17-1.53; P < 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P <0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P < 0.001). Conclusions: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
aging, coronary artery disease, inflammation, prevention, risk factor
in
Journal of the American College of Cardiology
volume
81
issue
20
pages
14 pages
publisher
Elsevier
external identifiers
  • pmid:37197843
  • scopus:85156162700
ISSN
0735-1097
DOI
10.1016/j.jacc.2023.03.401
language
English
LU publication?
yes
id
a1559a34-b8c3-4727-9466-37c08bc4c20e
date added to LUP
2023-08-10 11:46:52
date last changed
2024-05-18 03:48:28
@article{a1559a34-b8c3-4727-9466-37c08bc4c20e,
  abstract     = {{<p>Background: Clonal hematopoiesis of indeterminate potential (CHIP)—the age-related clonal expansion of blood stem cells with leukemia-associated mutations—is a novel cardiovascular risk factor. Whether CHIP remains prognostic in individuals with established atherosclerotic cardiovascular disease (ASCVD) is less clear. Objectives: This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. Methods: Individuals aged 40 to 70 years from the UK Biobank with established ASCVD and available whole-exome sequences were analyzed. The primary outcome was a composite of ASCVD events and all-cause mortality. Associations of any CHIP (variant allele fraction ≥2%), large CHIP clones (variant allele fraction ≥10%), and the most commonly mutated driver genes (DNMT3A, TET2, ASXL1, JAK2, PPM1D/TP53 [DNA damage repair genes], and SF3B1/SRSF2/U2AF1 [spliceosome genes]) with incident outcomes were compared using unadjusted and multivariable-adjusted Cox regression. Results: Of 13,129 individuals (median age: 63 years) included, 665 (5.1%) had CHIP. Over a median follow-up of 10.8 years, any CHIP and large CHIP at baseline were associated with adjusted HRs of 1.23 (95% CI: 1.10-1.38; P &lt; 0.001) and 1.34 (95% CI: 1.17-1.53; P &lt; 0.001), respectively, for the primary outcome. TET2 and spliceosome CHIP, especially large clones, were most strongly associated with adverse outcomes (large TET2 CHIP: HR: 1.89; 95% CI: 1.40-2.55; P &lt;0.001; large spliceosome CHIP: HR: 3.02; 95% CI: 1.95-4.70; P &lt; 0.001). Conclusions: CHIP is independently associated with adverse outcomes in individuals with established ASCVD, with especially high risks observed in TET2 and SF3B1/SRSF2/U2AF1 CHIP.</p>}},
  author       = {{Gumuser, Esra D. and Schuermans, Art and Cho, So Mi Jemma and Sporn, Zachary A. and Uddin, Md Mesbah and Paruchuri, Kaavya and Nakao, Tetsushi and Yu, Zhi and Haidermota, Sara and Hornsby, Whitney and Weeks, Lachelle D. and Niroula, Abhishek and Jaiswal, Siddhartha and Libby, Peter and Ebert, Benjamin L. and Bick, Alexander G. and Natarajan, Pradeep and Honigberg, Michael C.}},
  issn         = {{0735-1097}},
  keywords     = {{aging; coronary artery disease; inflammation; prevention; risk factor}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{20}},
  pages        = {{1996--2009}},
  publisher    = {{Elsevier}},
  series       = {{Journal of the American College of Cardiology}},
  title        = {{Clonal Hematopoiesis of Indeterminate Potential Predicts Adverse Outcomes in Patients With Atherosclerotic Cardiovascular Disease}},
  url          = {{http://dx.doi.org/10.1016/j.jacc.2023.03.401}},
  doi          = {{10.1016/j.jacc.2023.03.401}},
  volume       = {{81}},
  year         = {{2023}},
}