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Host Genetic Determinants of the Outcome of SAB by WES

ABSTRACT:

In this case-control study, Complicated Staphylococcus aureus (case) is defined as bacteremia plus endocarditis or bone/joint infection, and Uncomplicated Staphylococcus aureus (control) has no such complications and was cured at follow-up. We used whole exome sequencing to examine the cumulative effect of coding variants in each gene on risk of complicated SAB in a discovery sample of 168 SAB cases (84 Complicated SAB and 84 Uncomplicated SAB, frequency matched by age, sex and bacterial clonal complex). Then we evaluated the 334 most significantly associated genes and 8 biological candidate genes in a replication sample of 240 SAB cases (122 complicated and 118 uncomplicated, frequency matched by age, sex and bacterial clonal complex). All participants were white, non-Hispanic of European descent.

In the discovery sample, gene-based analysis using SKAT-O identified 334 genes associated with complicated SAB at p<3.5 x 10^-3;. Gene-based analysis of the 342 genes in the replication sample using SKATO identified one gene, GLS2 (GeneID: 27165), significantly associated with complicated SAB (p=1.2 x10^-4;) after Bonferroni correction. GLS2 is an interesting candidate gene for complicated SAB due to its role in regulating glutamine metabolism, a key factor in white blood cell proliferation and activation.

PROVIDER: phs001505 | dbGaP |

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001505.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs001505.SAB_WES.v1.p1.MULTI.pdf	Pdf
	manifest_phs001505.SAB_WES.v1.p1.c1.DS-GNB-IRB.pdf	Pdf
	datadict_v2.xsl	Other

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Project description:Raghunathan2009 - Genome-scale metabolic network of Salmonella typhimurium (iRR1083) This model is described in the article: Constraint-based analysis of metabolic capacity of Salmonella typhimurium during host-pathogen interaction. Raghunathan A, Reed J, Shin S, Palsson B, Daefler S. BMC Syst Biol 2009; 3: 38 Abstract: BACKGROUND: Infections with Salmonella cause significant morbidity and mortality worldwide. Replication of Salmonella typhimurium inside its host cell is a model system for studying the pathogenesis of intracellular bacterial infections. Genome-scale modeling of bacterial metabolic networks provides a powerful tool to identify and analyze pathways required for successful intracellular replication during host-pathogen interaction. RESULTS: We have developed and validated a genome-scale metabolic network of Salmonella typhimurium LT2 (iRR1083). This model accounts for 1,083 genes that encode proteins catalyzing 1,087 unique metabolic and transport reactions in the bacterium. We employed flux balance analysis and in silico gene essentiality analysis to investigate growth under a wide range of conditions that mimic in vitro and host cell environments. Gene expression profiling of S. typhimurium isolated from macrophage cell lines was used to constrain the model to predict metabolic pathways that are likely to be operational during infection. CONCLUSION: Our analysis suggests that there is a robust minimal set of metabolic pathways that is required for successful replication of Salmonella inside the host cell. This model also serves as platform for the integration of high-throughput data. Its computational power allows identification of networked metabolic pathways and generation of hypotheses about metabolism during infection, which might be used for the rational design of novel antibiotics or vaccine strains. This model is hosted on BioModels Database and identified by: MODEL1507180058. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Host Genetic Determinants of the Outcome of SAB by WES

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