An unbiased systems genetics approach to mapping genetic loci modulating susceptibility to severe streptococcal sepsis.

PLoS Pathogens
N F AbdeltawabMalak Kotb

Abstract

Striking individual differences in severity of group A streptococcal (GAS) sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL) on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%-30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases ...Continue Reading

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Citations

Aug 17, 2010·Archives de pédiatrie : organe officiel de la Sociéte française de pédiatrie·A FilleronE Jeziorski
Sep 5, 2009·The Journal of Clinical Investigation·James M Musser, Samuel A Shelburne
Feb 26, 2013·PloS One·Katariina Hannula-JouppiJuha Kere
May 12, 2012·Prostaglandins & Other Lipid Mediators·David M AronoffPeter Mancuso
Sep 20, 2011·Immunobiology·Christelle RobertDavid A Hume
Oct 27, 2015·Frontiers in Immunology·Christopher N LaRock, Victor Nizet
Oct 26, 2011·American Journal of Reproductive Immunology : AJRI·Katie L Mason, David M Aronoff
Aug 29, 2014·PLoS Pathogens·James A TsatsaronisMartina L Sanderson-Smith
Jul 12, 2016·PLoS Pathogens·Karthickeyan Chella KrishnanMalak Kotb
Oct 16, 2009·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Pierre Robert SmeestersAnne Vergison
Apr 2, 2014·Pathogens and Disease·Felicia D EmeryMark A Miller
Jul 21, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Oliver GoldmannEva Medina
Aug 6, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Katie L MasonDavid M Aronoff

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Methods Mentioned

BETA
PCR
GTPase
blood drawn

Software Mentioned

WebQTL
Gene Network ( GN )
GN

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