Genetic modification of inflammation and clonal hematopoiesis-associated cardiovascular risk
Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVD), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. CHIP was identified using whole exome sequencing data of blood DNA and modeled both as a composite and for common drivers (DNMT3A,TET2,ASXL1,andJAK2) separately. We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identifyIL1RAPas a potential key molecule for CHIP-associated CVD risk across genes and increasedAIM2gene expression leading to heightenedJAK2- andASXL1-associated CVD risks. We show that CRISPR- inducedAsxl1mutated murine macrophages have a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD protective effect ofIL10expression inASXL1CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides new evidence to support gene-specific strategies to address CHIP-associated CVD risk..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 19. Juni Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yu, Zhi [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| Themen: |
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| doi: |
10.1101/2022.12.08.22283237 |
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| PPN (Katalog-ID): |
XBI038123916 |
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| 520 | |a Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVD), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. CHIP was identified using whole exome sequencing data of blood DNA and modeled both as a composite and for common drivers (DNMT3A,TET2,ASXL1,andJAK2) separately. We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identifyIL1RAPas a potential key molecule for CHIP-associated CVD risk across genes and increasedAIM2gene expression leading to heightenedJAK2- andASXL1-associated CVD risks. We show that CRISPR- inducedAsxl1mutated murine macrophages have a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD protective effect ofIL10expression inASXL1CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides new evidence to support gene-specific strategies to address CHIP-associated CVD risk. | ||
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