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Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery.

ABSTRACT: Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors.In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies.We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice.These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes.

SUBMITTER: Albright J

PROVIDER: S-EPMC4142055 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery.

Albright Jody J Quizon Pamela M PM Lusis Aldons J AJ Bennett Brian J BJ

BMC medical genomics 20140812

<h4>Background</h4>Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors.<h4>Methods</h4>In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies.<h4>Results</h4>We identify 1 coexp ...[more]

PMID: 25115202

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Project description:The skin is the primary feeding site of ticks that infest livestock animals such as cattle. The highly specialised functions of skin at the molecular level may be a factor contributing to variation in susceptibility to tick infestation; but these remain to be well defined. The aim of this study was to investigate the bovine skin transcriptomic profiles of tick-naïve and tick-infested cattle and to uncover the gene expression networks that influence contrasting phenotypes of host resistance to ticks. RNA-Seq data was obtained from skin of Brangus cattle with high (n = 5) and low (n = 6) host resistance at 0 and 12 weeks following artificial tick challenge with Rhipicephalus australis larvae. No differentially expressed genes were detected pre-infestation between high and low resistance groups, but at 12-weeks there were 229 differentially expressed genes (DEGs; FDR < 0.05), of which 212 were the target of at least 1866 transcription factors (TFs) expressed in skin. Regulatory impact factor (RIF) analysis identified 158 significant TFs (P < 0.05) of which GRHL3, and DTX1 were also DEGs in the experiment. Gene term enrichment showed the significant TFs and DEGs were enriched in processes related to immune response and biological pathways related to host response to infectious diseases. Interferon Type 1-stimulated genes, including MX2, ISG15, MX1, OAS2 were upregulated in low host resistance steers after repeated tick challenge, suggesting dysregulated wound healing and chronic inflammatory skin processes contributing to host susceptibility to ticks. The present study provides an assessment of the bovine skin transcriptome before and after repeated tick challenge and shows that the up-regulation of pro-inflammatory genes is a prominent feature in the skin of tick-susceptible animals. In addition, the identification of transcription factors with high regulatory impact provides insights into the potentially meaningful gene-gene interactions involved in the variation of phenotypes of bovine host resistance to ticks.

Dataset Information

Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery.

Publications

Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery.

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