Whole Genome DNA and RNA Sequencing of Whole Blood Elucidates the Genetic Architecture of Gene Expression Underlying a Wide Range of Diseases

Liu, Chunyu; Joehanes, Roby; Ma, Jiantao; Huan, Tianxiao; Sun, Xianbang; Keshawarz, Amena; Sooda, Meera; Hwang, Shih‐Jen; Bui, Helena; Tejada, Brandon; Munson, Peter J.; Heard‐Costa, Nancy L.; Pitsillides, Achilleas N.; Peloso, Gina M.; Wang, Yuxuan; Vasan, Ramachandran S.; Demirkale, Cumhur Yusuf; Feolo, Mike; Sharopova, Nataliya; Levy, Dan

doi:10.1101/2022.04.13.22273841

Cited by 2 publications

(2 citation statements)

References 44 publications

(71 reference statements)

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“…Included in this study were 2,622 individuals from the Offspring and Gen 3 cohorts who had peripheral whole-blood samples collected and blood RNA sequenced at exams 9 and 2, respectively. For technical details for the blood draw and RNA-Seq, see Liu et al (71).…”

Section: Methodsmentioning

confidence: 99%

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

Yu¹,

Fidler²,

Ruan³

et al. 2023

Journal of Clinical Investigation

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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.

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Section: Methodsmentioning

confidence: 99%

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

Yu¹,

Fidler²,

Ruan³

et al. 2023

Journal of Clinical Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Included in this study are 2,622 individuals from the Offspring and Gen 3 cohorts who had their peripheral whole blood samples collected and blood RNA sequenced at exam 9 and 2, respectively. The technical details for the blood draw and RNA sequencing can be found at Liu et al 65 .…”

Section: Rna Sequencing (Rna-seq) Data Was Obtained From Two Transomi...mentioning

confidence: 99%

Genetic modification of inflammation and clonal hematopoiesis-associated cardiovascular risk

Fidler

Ruan

et al. 2022

Preprint

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View full text Add to dashboard Cite

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, and JAK2) separately. We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identify 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 risks. We show that CRISPR-induced Asxl1 mutated murine macrophages have a particularly heightened inflammatory response to AIM2 agonism. Our study provides new evidence to support gene-specific strategies to address CHIP-associated CVD risk.

show abstract

Whole Genome DNA and RNA Sequencing of Whole Blood Elucidates the Genetic Architecture of Gene Expression Underlying a Wide Range of Diseases

Cited by 2 publications

References 44 publications

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

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

Genetic modification of inflammation and clonal hematopoiesis-associated cardiovascular risk

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