Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing

Sardo, Valentina Lo; Chubukov, Pavel; Ferguson, William C.; Kumar, Aditya; Teng, Evan L.; Duran, Michael A.; Zhang, Lei; Cost, Gregory J.; Engler, Adam J.; Urnov, Fyodor D.; Topol, Eric J.; Torkamani, Ali; Baldwin, Kristin K.

doi:10.1016/j.cell.2018.11.014

Cited by 101 publications

(113 citation statements)

References 65 publications

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“…GWAS results have highlighted biological processes in the vessel wall as key drivers of coronary artery disease (CAD) 21 . Further, our own work has demonstrated the vascular wall to be involved in the most impactful genetic risk factor for CAD 22 . Our results here also demonstrate extensive differential expression in these cell types across anatomic locations.…”

Section: Resultsmentioning

confidence: 80%

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

Alsaigh¹,

Evans²,

Frankel

et al. 2020

Preprint

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Atherogenesis involves an interplay of inflammation, tissue remodeling and cellular transdifferentiation (CTD), making it especially difficult to precisely delineate its pathophysiology. Here we examine the single-cell transcriptome of entire atherosclerotic core (AC) plaques and patient-matched proximal adjacent (PA) portions of carotid artery tissue from patients undergoing carotid endarterectomy. We use a novel tissue dissociation strategy, single-cell RNA sequencing, and systems-biology approaches to analyze the transcriptional profiles of six main cell populations and identify key gene drivers of pathogenic biological processes in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Our results reveal an anatomic continuum whereby PA cells promote and respond to inflammatory processes and eventually transition through CTD into matrix-secreting cells in the AC. Inflammatory signaling in PA ECs is driven by IL6, while TNFa signaling defines inflammation in both PA ECs and VSMCs. Furthermore, we identify POSTN, SPP1 and IBSP in AC VSMCs, and ITLN1, SCX and S100A4 in AC ECs as key drivers of CTD in the atherosclerotic core. These results establish an anatomic framework for atherogenesis and suggest a site-specific strategy for disruption of disease progression.

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Section: Resultsmentioning

confidence: 80%

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

Alsaigh¹,

Evans²,

Frankel

et al. 2020

Preprint

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“…However, there are multiple ANRIL isoforms, including short, long and circular, and reports differ on which are specifically increased or decreased in CVD. In this regard, iPSC-derived VSMC lines from humans with risk haplotypes express higher levels of short ANRIL transcripts 13 . The ANRIL gene product upregulates metabolic genes in cultured cells, as well as stimulating VSMC proliferation 2,5,12 .…”

Section: Discussionmentioning

confidence: 99%

“…VSMCs generated by differentiation of iPSCs from humans homozygous for risk haplotypes in Chr9p21 show globally altered transcriptional networks, dysregulated adhesion, contraction and proliferation, with deletion of the risk haplotype rescuing the phenotype 13 Figure 6).…”

Section: Vsmcs Generated From Ipscs From Chr9p21 Risk Haplotypes Showmentioning

confidence: 99%

“…Here, plasma from a prospective cohort (Northwick Park Heart Study II, NPHSII) which recruited ~3,000 men aged 50 -61 years clinically free of CHD in 1990-1991, was analysed using targeted and untargeted lipidomics, followed by validation, metabolic correlation and network analysis 10,11 . Then, gene transcription for lipid metabolic enzymes was mined in data from a cellular ANRIL knockdown study, and from vascular smooth muscle cells differentiated from iPSCs obtained from individuals carrying Chr9p21 risk SNPs 12,13 .…”

Section: Introductionmentioning

confidence: 99%

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Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274

Meckelmann

Hawksworth

White

et al. 2019

Preprint

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AbstractAimsCommon chromosome 9p21 SNPs increase coronary heart disease (CHD) risk, independent of “traditional lipid risk factors”. However, lipids comprise large numbers of structurally-related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here we applied lipidomic and genomic approaches to three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer ∼30% elevated CHD risk associated with altered expression of ANRIL, a long ncRNA.Methods and ResultsUntargeted and targeted lipidomics was applied to plasma samples from Northwick Park Heart Study II (NPHSII) homozygotes for AA or GG in rs10757274. Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). Five other risk SNPs did not show this phenotype. Correlation and network analysis showed that lysoPL-lysoPA interconversion was uncoupled from ATX in GG, indicating metabolic dysregulation. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK293 cells was mined. Significantly-altered expression of several lysoPL/lysoPA metabolising enzymes was found (MBOAT2, PLA2G4C, LPCAT2, ACSL6, PNPLA2, PLBD1, PLPP1, PLPP2 and PLPPR2). Next, vascular smooth muscle cells differentiated from iPSCs of individuals homozygous for Chr9p21 risk SNPs were examined. Here, the presence of risk alleles was associated with altered expression of several lysoPL/lysoPA enzymes. Importantly, for several, deletion of the risk locus fully or partially reversed their expression to non-risk haplotype levels: ACSL3, DGKA, PLA2G2A, LPCAT2, LPL, PLA2G3, PNPLA3, PLA2G12A LIPC, LCAT, PLA2G6, ACSL1, MBOAT2.ConclusionA Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their enzymatic metabolism. Lipid metabolites and genomic pathways associated with CHD pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.One sentence summaryInflammatory phospholipid metabolism defines a cardiovascular disease SNP

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“…The function of ANRIL remains incompletely understood, but a number of studies suggest ANRIL regulates cell proliferation and senescence of VSMCs either by Alu motif-dependent trans regulation of atherorelevant genes through polycomb protein complexes [95], or by regulating miR-181a/Sirt1 [96]. Using iPSC-derived VSMCs, VSMCs carrying 9p21.3 risk allele exhibit globally altered transcriptional networks that intersect with previously identified coronary artery disease (CAD) risk genes and pathways and risk-dependent gene networks drive cell state instability, partially through ANRIL [97]. Deleting the risk haplotype rescues VSMC stability, while expression ANRIL induces risk phenotypes in non-risk VSMCs.…”

Section: Lncrnas In Vascular Smooth Muscle Cellsmentioning

confidence: 99%

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

Yeh

Chang

et al. 2020

J Biomed Sci

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With the advances in deep sequencing-based transcriptome profiling technology, it is now known that human genome is transcribed more pervasively than previously thought. Up to 90% of the human DNA is transcribed, and a large proportion of the human genome is transcribed as long noncoding RNAs (lncRNAs), a heterogenous group of non-coding transcripts longer than 200 nucleotides. Emerging evidence suggests that lncRNAs are functional and contribute to the complex regulatory networks involved in cardiovascular development and diseases. In this article, we will review recent evidence on the roles of lncRNAs in the biological processes of cardiovascular development and disorders. The potential applications of lncRNAs as biomarkers and targets for therapeutics are also discussed.

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Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing

Cited by 101 publications

References 65 publications

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

Decoding the transcriptome of atherosclerotic plaque at single-cell resolution

Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

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