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Search: WFRF:(Kent Peter) > (2020-2024) > Genetic modificatio...

Genetic modification of inflammation- and clonal hematopoiesis-associated cardiovascular risk

Yu, Zhi (author)
Broad Institute,Massachusetts General Hospital
Fidler, Trevor P. (author)
Columbia University
Ruan, Yunfeng (author)
Broad Institute
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Vlasschaert, Caitlyn (author)
Nakao, Tetsushi (author)
Massachusetts General Hospital,Dana-Farber Cancer Institute,Broad Institute,Harvard Medical School
Uddin, Md Mesbah (author)
Broad Institute,Massachusetts General Hospital
Mack, Taralynn (author)
Vanderbilt University Medical Center
Niroula, Abhishek (author)
Lund University,Lunds universitet,Hematogenomics,Forskargrupper vid Lunds universitet,Lund University Research Groups,Broad Institute,Dana-Farber Cancer Institute
Brett Heimlich, J. (author)
Vanderbilt University Medical Center
Zekavat, Seyedeh M. (author)
Broad Institute,Massachusetts General Hospital,Massachusetts Eye and Ear Infirmary
Gibson, Christopher J. (author)
Dana-Farber Cancer Institute
Griffin, Gabriel K. (author)
Broad Institute,Brigham and Women's Hospital / Harvard Medical School,Dana-Farber Cancer Institute
Wang, Yuxuan (author)
Boston University
Peloso, Gina M. (author)
Boston University
Heard-Costa, Nancy (author)
Boston University,Framingham Heart Study
Levy, Daniel (author)
Framingham Heart Study,National Heart Lung and Blood Institute
Vasan, Ramachandran S. (author)
Boston University,Framingham Heart Study
Aguet, François (author)
Broad Institute
Ardlie, Kristin G. (author)
Broad Institute
Taylor, Kent D. (author)
Harbor–UCLA Medical Center
Rich, Stephen S. (author)
University of Virginia School of Medicine
Rotter, Jerome I. (author)
Harbor–UCLA Medical Center
Libby, Peter (author)
Harvard Medical School
Jaiswal, Siddhartha (author)
Stanford University School of Medicine
Ebert, Benjamin L. (author)
Dana-Farber Cancer Institute,Broad Institute
Bick, Alexander G. (author)
Vanderbilt University Medical Center,Broad Institute
Tall, Alan R. (author)
Columbia University
Natarajan, Pradeep (author)
Broad Institute,Massachusetts General Hospital,Harvard Medical School
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 (creator_code:org_t)
2023
2023
English.
In: Journal of Clinical Investigation. - 0021-9738. ; 133:18
Related links:
http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVDprotective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medical Genetics (hsv//eng)

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