Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome Analysis in Patients with Progressive Coronary Artery Disease

ABSTRACT: The identification of classic risk factors for coronary artery disease unveiled pathophysiologic mechanisms of atherosclerosis. Among them, inflammation as a systemic process measurable in peripheral blood plays a central role in plaque progression. However, other mechanisms of plaque progression remain to be fully understood. Therefore, this study sought to further investigate systemic correlates of plaque progression by global gene expression in peripheral blood. Microrarray gene expression analysis revealed 93 genes differentially expressed between the groups, of which 23 genes have no known function. Among the remaining 70 genes, 10 (14%) were identified to be associated with progenitor and pluripotent cells whereas only 3 genes (4%) had been associated with atherosclerosis. A risk prediction gene signature was developed by a multivariable statistical approach model integrating comprehensive laboratory and clinical patient data. This signature identified plaque progression with 81% sensitivity and 80% specificity (AUC: 0.86) for new patients, as estimated by resampling techniques. Array results were validated by qPCR for the genes ankyrin-2 (ANK2) and glutathione S-transferase theta 1 (GSTT1). In conclusion, patients with pogressive coronary artery disease despite good risk factor control exhibit particular gene expression patterns in peripheral blood. Understanding the functional implications of the observed changes might help to design new approaches to control atherosclerosis progression. From a large database of 45,727 coronary angiograms, peripheral blood was drawn from two patient groups with good risk factor control, but different clinical evolution: First, 16 patients with significant lesion progression leading to repeated coronary interventions and second, 16 patients with angiographically documented stable courses.

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas Nuehrenberg

PROVIDER: E-GEOD-34822 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcriptome analysis in patients with progressive coronary artery disease: identification of differential gene expression in peripheral blood.

Nührenberg Thomas G TG Langwieser Nicole N Binder Harald H Kurz Thorsten T Stratz Christian C Kienzle Rolf-Peter RP Trenk Dietmar D Zohlnhöfer-Momm Dietlind D Neumann Franz-Josef FJ

Journal of cardiovascular translational research 20121129 1

Inflammation as a systemic process plays a central role in atherosclerotic plaque progression (PP). Here we investigated other systemic correlates of PP by global gene expression profiling (GEP) in peripheral blood. From a database of 45,727 coronary angiograms, we identified two patient groups with good risk factor control, but different clinical evolution: First, 16 patients had significant PP leading to repeated coronary interventions, and second, 16 patients had angiographically documented s ...[more]

PMID: 23188564

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Project description:Background: Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP), particularly in DNMT3A, TET2, and JAK2, are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. However, whether CHIP is associated with increased risk of peripheral artery disease (PAD) remains unknown. In addition, chemotherapy frequently causes mutations in DNA Damage Repair (DDR) genes TP53 and PPM1D, and whether CHIP caused by somatic mutations in DDR genes results in increased risk of atherosclerosis is unclear. We sought to test whether CHIP, and CHIP caused by DDR genes, associates with incident peripheral artery disease (PAD) and atherosclerosis. Methods: We identified CHIP among 50,122 exome sequences in individuals from UK and Mass General Brigham Biobanks and tested CHIP status (N=2,851) with incident PAD and atherosclerosis across multiple arterial beds. To mimic the human scenario of clonal hematopoiesis and test whether the expansion of p53-deficient hematopoietic cells contributes to atherosclerosis, a competitive bone marrow transplantation (BMT) strategy was used to generate atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% Trp53-/- hematopoietic cells (20% KO-BMT mice). We then evaluated aortic plaque burden and plaque macrophage accumulation 12 weeks after grafting. Results: CHIP associated with incident PAD (HR 1.7; P=2.2x10-5) and atherosclerosis in multiple beds (HR 1.3; P=9.7x10-5), with increased risk among individuals with DDR CHIP (HR 2.0; P=0.0084). Among atherosclerosis-prone Ldlr null mice, the p53 -/- 20% KO-BMT mice demonstrated increased aortic plaque size (p=0.013) and accumulation of p53-/- plaque macrophages (P<0.001), driven by an abundance of p53-deficient plaque macrophages. The expansion of p53-deficient cells did not affect the expression of the pro-inflammatory cytokines IL-6 and IL-1β in the atherosclerotic aortic wall. Conclusions: Our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system, with evidence of increased plaque among p53 -/- 20% KO-BMT mice via expansion of plaque macrophages. These observations provide new insight into the link between CHIP and cardiovascular disease, and lend human genetic support to the concept that post-cytotoxic chemotherapy patients may benefit from surveillance for atherosclerotic conditions in addition to therapy-related myeloid neoplasms.

Dataset Information

Transcriptome Analysis in Patients with Progressive Coronary Artery Disease

Publications

Transcriptome analysis in patients with progressive coronary artery disease: identification of differential gene expression in peripheral blood.

Similar Datasets

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