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

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...

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Published in:Journal of the American College of Cardiology Vol. 81; no. 20; p. 1996
Main Authors: Gumuser, Esra D, Schuermans, Art, Cho, So Mi Jemma, Sporn, Zachary A, Uddin, Md Mesbah, Paruchuri, Kaavya, Nakao, Tetsushi, Yu, Zhi, Haidermota, Sara, Hornsby, Whitney, Weeks, Lachelle D, Niroula, Abhishek, Jaiswal, Siddhartha, Libby, Peter, Ebert, Benjamin L, Bick, Alexander G, Natarajan, Pradeep, Honigberg, Michael C
Format: Journal Article
Language:English
Published: United States 23.05.2023
Subjects:
Atherosclerosis - genetics
Cardiovascular Diseases - epidemiology
Cardiovascular Diseases - genetics
Clonal Hematopoiesis - genetics
Hematopoiesis - genetics
Humans
Middle Aged
Mutation
Splicing Factor U2AF - genetics
coronary artery disease
aging
inflammation
risk factor
prevention
ISSN:1558-3597, 1558-3597
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Summary: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. This study tested whether CHIP predicts adverse outcomes in individuals with established ASCVD. 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. 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). 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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ISSN:1558-3597
1558-3597
DOI:10.1016/j.jacc.2023.03.401