Dataset Information

Tissue-specific Network Analysis of Genetic Variants Associated with Coronary Artery Disease.

ABSTRACT: Coronary artery disease (CAD) is a leading cause of death worldwide. Recent genome-wide association studies have identified more than one hundred susceptibility loci associated with CAD. However, the underlying mechanism of these genetic loci to CAD susceptibility is still largely unknown. We performed a tissue-specific network analysis of CAD using the summary statistics from one of the largest genome-wide association studies. Variant-level associations were summarized into gene-level associations, and a CAD-related interaction network was built using experimentally validated gene interactions and gene coexpression in coronary artery. The network contained 102 genes, of which 53 were significantly associated with CAD. Pathway enrichment analysis revealed that many genes in the network were involved in the regulation of peripheral arteries. In summary, we performed a tissue-specific network analysis and found abnormalities in the peripheral arteries might be an important pathway underlying the pathogenesis of CAD. Future functional characterization might further validate our findings and identify potential therapeutic targets for CAD.

SUBMITTER: Miao X

PROVIDER: S-EPMC6068195 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Tissue-specific Network Analysis of Genetic Variants Associated with Coronary Artery Disease.

Miao Xiao X Chen Xinlin X Xie Zhijun Z Lin Honghuang H

Scientific reports 20180731 1

Coronary artery disease (CAD) is a leading cause of death worldwide. Recent genome-wide association studies have identified more than one hundred susceptibility loci associated with CAD. However, the underlying mechanism of these genetic loci to CAD susceptibility is still largely unknown. We performed a tissue-specific network analysis of CAD using the summary statistics from one of the largest genome-wide association studies. Variant-level associations were summarized into gene-level associati ...[more]

PMID: 30065343

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Project description:BACKGROUND:The relation between burden of risk factors, familial coronary artery disease (CAD), and known genetic variants underlying CAD and low-density lipoprotein cholesterol (LDL-C) levels is not well-explored in clinical samples. We aimed to investigate the association of these measures with age at onset of CAD requiring revascularizations in a clinical sample of patients undergoing first-time coronary angiography. METHODS:1599 individuals (mean age 64 years [min-max 29-96 years], 28% women) were genotyped (from blood drawn as part of usual clinical care) in the Copenhagen area (2010-2014). The burden of common genetic variants was measured as aggregated genetic risk scores (GRS) of single nucleotide polymorphisms (SNPs) discovered in genome-wide association studies. RESULTS:Self-reported familial CAD (prevalent in 41% of the sample) was associated with -3.2 years (95% confidence interval -4.5, -2.2, p<0.0001) earlier need of revascularization in sex-adjusted models. Patients with and without familial CAD had similar mean values of CAD-GRS (unweighted scores 68.4 vs. 68.0, p = 0.10, weighted scores 67.7 vs. 67.5, p = 0.49) and LDL-C-GRS (unweighted scores 58.5 vs. 58.3, p = 0.34, weighted scores 63.3 vs. 61.1, p = 0.41). The correlation between the CAD-GRS and LDL-C-GRS was low (r = 0.14, p<0.001). In multivariable adjusted regression models, each 1 standard deviation higher values of LDL-C-GRS and CAD-GRS were associated with -0.70 years (95% confidence interval -1.25, -0.14, p = 0.014) and -0.51 years (-1.07, 0.04, p = 0.07) earlier need for revascularization, respectively. CONCLUSIONS:Young individuals presenting with CAD requiring surgical interventions had a higher genetic burden of SNPs relating to LDL-C and CAD (although the latter was statistically non-significant), compared with older individuals. However, the absolute difference was modest, suggesting that genetic screening can currently not be used as an effective prediction tool of when in life a person will develop CAD. Whether undiscovered genetic variants can still explain a "missing heritability" in early-onset CAD warrants more research.

Dataset Information

Tissue-specific Network Analysis of Genetic Variants Associated with Coronary Artery Disease.

Publications

Tissue-specific Network Analysis of Genetic Variants Associated with Coronary Artery Disease.

Similar Datasets

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