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Gene expression signatures of coronary heart disease.

ABSTRACT: OBJECTIVE:To identify transcriptomic biomarkers of coronary heart disease (CHD) in 188 cases with CHD and 188 age- and sex-matched controls who were participants in the Framingham Heart Study. APPROACH AND RESULTS:A total of 35 genes were differentially expressed in cases with CHD versus controls at false discovery rate<0.5, including GZMB, TMEM56, and GUK1. Cluster analysis revealed 3 gene clusters associated with CHD, 2 linked to increased erythrocyte production and a third to reduced natural killer and T cell activity in cases with CHD. Exon-level results corroborated and extended the gene-level results. Alternative splicing analysis suggested that GUK1 and 38 other genes were differentially spliced in cases with CHD versus controls. Gene Ontology analysis linked ubiquitination and T-cell-related pathways with CHD. CONCLUSIONS:Two bioinformatically defined groups of genes show consistent associations with CHD. Our findings are consistent with the hypotheses that hematopoesis is upregulated in CHD, possibly reflecting a compensatory mechanism, and that innate immune activity is disrupted in CHD or altered by its treatment. Transcriptomic signatures may be useful in identifying pathways associated with CHD and point toward novel therapeutic targets for its treatment and prevention.

SUBMITTER: Joehanes R

PROVIDER: S-EPMC3684247 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Gene expression signatures of coronary heart disease.

Joehanes Roby R Ying Saixia S Huan Tianxiao T Johnson Andrew D AD Raghavachari Nalini N Wang Richard R Liu Poching P Woodhouse Kimberly A KA Sen Shurjo K SK Tanriverdi Kahraman K Courchesne Paul P Freedman Jane E JE O'Donnell Christopher J CJ Levy Daniel D Munson Peter J PJ

Arteriosclerosis, thrombosis, and vascular biology 20130328 6

<h4>Objective</h4>To identify transcriptomic biomarkers of coronary heart disease (CHD) in 188 cases with CHD and 188 age- and sex-matched controls who were participants in the Framingham Heart Study.<h4>Approach and results</h4>A total of 35 genes were differentially expressed in cases with CHD versus controls at false discovery rate<0.5, including GZMB, TMEM56, and GUK1. Cluster analysis revealed 3 gene clusters associated with CHD, 2 linked to increased erythrocyte production and a third to r ...[more]

PMID: 23539218

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Project description:Genome-wide association studies have identified a coronary artery disease (CAD) risk locus in a non-coding region at 9p21.3, the nearest genes being CDKN2A and CDKN2B. To understand the pathways by which this locus might influence CAD susceptibility, we investigated associations between the 9p21.3 risk genotype and global gene expression in heart tissue from donors with no diagnosed heart disease (n?=?108, predominant cause of death, cerebral vascular accident) and in carotid plaque (n?=?106), aorta (n?=?104) and mammary artery (n?=?88) tissues from heart valve and carotid endarterectomy patients. Genotyping was performed with Taqman assays and Illumina arrays, and gene expression profiles generated with Affymetrix microarrays. Associations were analyzed with an additive genetic model. In heart tissue, 46 genes were putatively altered in association with the 9p21.3 risk allele (70% down-regulated, fold-change >1.1 per allele, p<0.05 adjusted for age, gender, ethnicity, cause of death). These genes were enriched for biomarkers of myocardial infarction (p?=?1.53×10(-9)), response to wounding (p?=?2.65×10(-10)) and inflammatory processes (p<1.97×10(-7)). Among the top 10 most down-regulated genes, 7 genes shared a set of transcription factor binding sites within conserved promoter regions (p<1.14×10(-5)), suggesting they may be co-regulated. Canonical pathway modelling of the most differentially expressed transcripts across all tissues (154 genes, 60% down-regulated, fold-change >1.1 per allele, p<0.01) showed that 75% of the genes could be transcriptionally regulated through the cell cycle G1 phase progression pathway (p<1.08×10(-258)), in which CDKN2A and CDKN2B play a regulatory role. These data suggest that the cell cycle G1 phase progression pathway is activated in individuals with the 9p21.3 risk allele. This may contribute to a proliferative phenotype that promotes adverse cardiac hypertrophy and vascular remodeling, leading to an increased CAD risk.

Project description:BackgroundHeart failure (HF) with preserved ejection fraction (HFpEF) constitutes half of all HF but lacks effective therapy. Understanding of its myocardial biology remains limited because of a paucity of heart tissue molecular analysis.MethodsWe performed RNA sequencing on right ventricular septal endomyocardial biopsies prospectively obtained from patients meeting consensus criteria for HFpEF (n=41) contrasted with right ventricular septal tissue from patients with HF with reduced ejection fraction (HFrEF, n=30) and donor controls (n=24). Principal component analysis and hierarchical clustering tested for transcriptomic distinctiveness between groups, effect of comorbidities, and differential gene expression with pathway enrichment contrasted HF groups and donor controls. Within HFpEF, non-negative matrix factorization and weighted gene coexpression analysis identified molecular subgroups, and the resulting clusters were correlated with hemodynamic and clinical data.ResultsPatients with HFpEF were more often women (59%), African American (68%), obese (median body mass index 41), and hypertensive (98%), with clinical HF characterized by 65% New York Heart Association Class III or IV, nearly all on a loop diuretic, and 70% with a HF hospitalization in the previous year. Principal component analysis separated HFpEF from HFrEF and donor controls with minimal overlap, and this persisted after adjusting for primary comorbidities: body mass index, sex, age, diabetes, and renal function. Hierarchical clustering confirmed group separation. Nearly half the significantly altered genes in HFpEF versus donor controls (1882 up, 2593 down) changed in the same direction in HFrEF; however, 5745 genes were uniquely altered between HF groups. Compared with controls, uniquely upregulated genes in HFpEF were enriched in mitochondrial adenosine triphosphate synthesis/electron transport, pathways downregulated in HFrEF. HFpEF-specific downregulated genes engaged endoplasmic reticulum stress, autophagy, and angiogenesis. Body mass index differences largely accounted for HFpEF upregulated genes, whereas neither this nor broader comorbidity adjustment altered pathways enriched in downregulated genes. Non-negative matrix factorization identified 3 HFpEF transcriptomic subgroups with distinctive pathways and clinical correlates, including a group closest to HFrEF with higher mortality, and a mostly female group with smaller hearts and proinflammatory signaling. These groupings remained after sex adjustment. Weighted gene coexpression analysis yielded analogous gene clusters and clinical groupings.ConclusionsHFpEF exhibits distinctive broad transcriptomic signatures and molecular subgroupings with particular clinical features and outcomes. The data reveal new signaling targets to consider for precision therapeutics.

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Gene expression signatures of coronary heart disease.

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Gene expression signatures of coronary heart disease.

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