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

Nourtan F. Abdeltawab, Ramy K. Aziz, Rita Kansal, Sarah L. Rowe, Yin Su, Lidia Gardner, Charity Brannen, Mohammed M. Nooh, Ramy R. Attia, Hossam A. Abdelsamed, William L. Taylor, Lu Lu, Robert Williams, Malak Kotb

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases.

Original languageEnglish (US)
Article numbere1000042
JournalPLoS Pathogens
Volume4
Issue number4
DOIs
StatePublished - Apr 1 2008

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Genetic Loci
Sepsis
Quantitative Trait Loci
Superantigens
Gene Ontology
Chromosomes, Human, Pair 2
Gene Regulatory Networks
Virulence Factors
Bacterial Infections
Individuality
Communicable Diseases
Genotype
Bacteria
Phenotype
Gene Expression
Genes

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Abdeltawab, N. F., Aziz, R. K., Kansal, R., Rowe, S. L., Su, Y., Gardner, L., ... Kotb, M. (2008). An unbiased systems genetics approach to mapping genetic loci modulating susceptibility to severe streptococcal sepsis. PLoS Pathogens, 4(4), [e1000042]. https://doi.org/10.1371/journal.ppat.1000042

An unbiased systems genetics approach to mapping genetic loci modulating susceptibility to severe streptococcal sepsis. / Abdeltawab, Nourtan F.; Aziz, Ramy K.; Kansal, Rita; Rowe, Sarah L.; Su, Yin; Gardner, Lidia; Brannen, Charity; Nooh, Mohammed M.; Attia, Ramy R.; Abdelsamed, Hossam A.; Taylor, William L.; Lu, Lu; Williams, Robert; Kotb, Malak.

In: PLoS Pathogens, Vol. 4, No. 4, e1000042, 01.04.2008.

Research output: Contribution to journalArticle

Abdeltawab, NF, Aziz, RK, Kansal, R, Rowe, SL, Su, Y, Gardner, L, Brannen, C, Nooh, MM, Attia, RR, Abdelsamed, HA, Taylor, WL, Lu, L, Williams, R & Kotb, M 2008, 'An unbiased systems genetics approach to mapping genetic loci modulating susceptibility to severe streptococcal sepsis', PLoS Pathogens, vol. 4, no. 4, e1000042. https://doi.org/10.1371/journal.ppat.1000042
Abdeltawab, Nourtan F. ; Aziz, Ramy K. ; Kansal, Rita ; Rowe, Sarah L. ; Su, Yin ; Gardner, Lidia ; Brannen, Charity ; Nooh, Mohammed M. ; Attia, Ramy R. ; Abdelsamed, Hossam A. ; Taylor, William L. ; Lu, Lu ; Williams, Robert ; Kotb, Malak. / An unbiased systems genetics approach to mapping genetic loci modulating susceptibility to severe streptococcal sepsis. In: PLoS Pathogens. 2008 ; Vol. 4, No. 4.
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