Resumen
Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
Idioma original | English (US) |
---|---|
Páginas (desde-hasta) | 788-797 |
Número de páginas | 10 |
Publicación | Stroke |
Volumen | 29 |
N.º | 2 |
DOI | |
Estado | Published - mar 1 2022 |
ASJC Scopus subject areas
- Clinical Neurology
- Cardiology and Cardiovascular Medicine
- Advanced and Specialized Nursing
Acceder al documento
Otros archivos y enlaces
Huella
Profundice en los temas de investigación de 'Clonal Hematopoiesis Is Associated with Higher Risk of Stroke'. En conjunto forman una huella única.Citar esto
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Clonal Hematopoiesis Is Associated with Higher Risk of Stroke. / Bhattacharya, Romit; Zekavat, Seyedeh M.; Haessler, Jeffrey et al.
En: Stroke, Vol. 29, N.º 2, 01.03.2022, p. 788-797.Resultado de la investigación: Article › revisión exhaustiva
}
TY - JOUR
T1 - Clonal Hematopoiesis Is Associated with Higher Risk of Stroke
AU - Bhattacharya, Romit
AU - Zekavat, Seyedeh M.
AU - Haessler, Jeffrey
AU - Fornage, Myriam
AU - Raffield, Laura
AU - Uddin, Md Mesbah
AU - Bick, Alexander G.
AU - Niroula, Abhishek
AU - Yu, Bing
AU - Gibson, Christopher
AU - Griffin, Gabriel
AU - Morrison, Alanna C.
AU - Psaty, Bruce M.
AU - Longstreth, William T.
AU - Bis, Joshua C.
AU - Rich, Stephen S.
AU - Rotter, Jerome I.
AU - Tracy, Russell P.
AU - Correa, Adolfo
AU - Seshadri, Sudha
AU - Johnson, Andrew
AU - Collins, Jason M.
AU - Hayden, Kathleen M.
AU - Madsen, Tracy E.
AU - Ballantyne, Christie M.
AU - Jaiswal, Siddhartha
AU - Ebert, Benjamin L.
AU - Kooperberg, Charles
AU - Manson, Joann E.
AU - Whitsel, Eric A.
AU - Natarajan, Pradeep
AU - Reiner, Alexander P.
N1 - Funding Information: Dr Bhattacharya reports consulting fees from Casana Care, Inc, unrelated to the present work. Dr Bick serves as a scientific advisor to Foresite Labs, reports stock holdings in TenSixteenBio, and compensation from TenSixteenBio. Dr Niroula reports grants from Knut och Alice Wallenbergs Stiftelse. Dr Psaty serves on the Yale Open Data Access Project funded by Johnson & Johnson. Dr Jaiswal has received consulting fees from AVRO Bio, Genentech, Novartis, and Foresite Labs. Dr Ebert has received research funding from Celgene, Deerfield, and Novartis and consulting fees from GRAIL. He serves on the scientific advisory boards and holds equity in Skyhawk Therapeutics, Exo Therapeutics, and Neomorph. Dr Natarajan reports prior grants from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Apple, AstraZeneca, Genentech, Blackstone Life Sciences, Foresite Labs, and Novartis; a patent issued for helical synthetic peptides that stimulates cellular cholesterol efflux licensed to Artery Therapeutics; and spousal employment at Vertex, unrelated to the present work. The other authors report no conflicts. Funding Information: Dr Bhattacharya is supported by the John S. LaDue Memorial Fellowship in Cardiovascular Medicine at the Harvard Medical School, and this work was additionally supported by the National Institutes of Health (NIH) Training Grant T32HL007208. S.M. Zekavat is supported by the NIH National Heart, Lung, and Blood Institute (NHLBI; 1F30HL149180-01) and the NIH Medical Scientist Training Program Training Grant (T32GM136651). Dr Fornage is supported by NS114045 and NS100605. Dr Raffield is supported by the National Center for Advancing Translational Sciences, NIH, through grant KL2TR002490 and by T32HL129982. Dr Bick is supported by a Burroughs Wellcome Foundation career award for medical scientists, the EvansMDS Foundation, RUNX1 research program, and an NIH Director’s Early Independence Award from the NIH Common Fund (DP5 OD029586). Dr Yu is supported by the NIH grant R01 HL148050. Dr Niroula is supported by the Knut and Alice Wallenberg Foundation (KAW2017.0436). Dr Gibson is supported by the Damon Runyon Cancer Research Foundation. Drs Psaty, Bis, Tracy, and Longstreth note their support via contracts for the Cardiovascular Health Study (noted below). Dr Rotter is supported by Trans-Omics in Precision Medicine (TOPMed) and MESA (Multi-Ethnic Study of Atherosclerosis) funding detailed below. Dr Correa is supported by HHSN268201800010I, R01 R01 HL143224, R01 HL142599, R01 AG066134, R01 HL143295, R01 HL146636, R01 AG0624, CC10310/SP13991, AWD-000969, R01 AG067513, R01 HL150170-01A, and R01 HL150170-01A1. Dr Seshadri is supported by R01s NS017950, AG059421, RF1AG059421, U01 AG052409, and AG066546. Dr Johnson is supported by the NHLBI Intramural Research funding. Dr Hayden is supported by the NIH grants R01 HL148565, R01 AG058969, NHLBI-WH-11-10, and HHSN271201700002C. Dr Ballantyne is supported by the NIH grant R01 HL148050. Dr Jaiswal is supported by DP2-HL157540 and R01-HL148565. Dr Kooperberg is supported by the NIH grants R01 HL148565 and R01 HL136574. Dr Manson is supported by R01 HL034594, R01 AT011729, and HHSN268201100001C and Mars Edge. Dr Whitsel is supported by the NIH grant R01-HL148565 and contract 75N92019R0031. Dr Ebert is supported by the Howard Hughes Medical Institute. Dr Reiner is supported by NIH grants R01 HL148565 and R01 HL136574. Dr Natarajan is supported by NIH grants R01 HL148050, R01 HL151283, and R01 HL148565. Dr Natarajan is additionally supported by Fondation Leducq TNE-18CVD04. The UK Biobank analyses were conducted using application 7089. “Building on GWAS for NHLBI Diseases: the US CHARGE Consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (5RC2HL102419). Data for “Building on GWAS for NHLBI Diseases: the US CHARGE Consortium” were provided by Eric Boerwinkle on behalf of the ARIC study (Atherosclerosis Risk in Communities), L. Adrienne Cupples, principal investigator for the Framingham Heart Study, and Bruce Psaty, principal investigator for the Cardiovascular Health Study. Sequencing was performed at the Baylor College of Medicine Human Genome Sequencing Center and supported by the National Human Genome Research Institute grants U54 HG003273 and UM1 HG008898. Whole-genome sequencing (WGS) for the TOPMed program was supported by the NHLBI. WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393; U01HL-120393; contract HHSN268180001I). The MESA project is supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Also supported, in part, by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756. The WHI program is funded by the NHLBI, NIH, US Department of Health and Human Services through contracts 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005. The ARIC study has been funded in whole or in part with Federal funds from the NHLBI, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. The Framingham Heart Study is conducted and supported by the NHLBI in collaboration with the Boston University (contract No. HHSN26820150001I, 75N92019D00031, and HC 25195), and its contract with Affymetrix, Inc, for genome-wide genotyping services (contract No. N02-HL-6-4278), for quality control by Framingham Heart Study investigators using genotypes in the SNP Health Association Resource project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis computing resources at the Boston University Medical Campus. Ascertainment of phenotypic data in the FHS was funded by AG054076, NS 017950, and AG049607. Cardiovascular Health Study: this research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006 and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging. A full list of principal CHS (Cardiovascular Health Study) investigators and institutions can be found at CHS-NHLBI.org. JHS (Jackson Heart Study) is supported and conducted in collaboration with the Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. The authors also wish to thank the staffs and participants of the JHS. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI; the NIH; or the US Department of Health and Human Services. Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
AB - Background and Purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke. Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (DNMT3A, TET2, and ASXL1) with any stroke, ischemic stroke, and hemorrhagic stroke. Results: CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 [95% CI, 1.03-1.27]; P=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 [95% CI, 1.01-1.51]; P=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results, TET2 showed the strongest association with total stroke and ischemic stroke, whereas DMNT3A and TET2 were each associated with increased risk of hemorrhagic stroke. Conclusions: CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
KW - brain ischemia
KW - cardiovascular diseases
KW - clonal hematopoiesis
KW - humans
KW - prospective studies
UR - http://www.scopus.com/inward/record.url?scp=85124496427&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124496427&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.121.037388
DO - 10.1161/STROKEAHA.121.037388
M3 - Article
C2 - 34743536
AN - SCOPUS:85124496427
SN - 0039-2499
VL - 29
SP - 788
EP - 797
JO - Stroke
JF - Stroke
IS - 2
ER -