An Unbiased Systems Genetics Approach to Mapping Genetic Loci Modulating Susceptibility to Severe Streptococcal Sepsis

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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. Group A streptococci (GAS) cause a wide variety of human diseases ranging from mild pharyngitis to streptococcal toxic shock syndrome and necrotizing faciitis. Our previous studies have shown that host immunogenetic variation can dictate the clinical outcome of GAS sepsis. As in most human disease, GAS sepsis is likely to be affected by complex interactions between more than one polymorphic gene. We addressed this issue in our study where we present an approach that allowed us to identify multi genetic factors that likely contribute to sepsis severity. We mapped susceptibility to severe GAS sepsis to quantitative trait loci on Chromosome 2 using a panel of genetically diverse inbred mice. The mapped regions have high single nucleotide polymorphism (SNP) density that harbor genes known to play an important role in innate immune response to bacteria. Several of those genes are differentially expressed between susceptible and resistant strains of mice. Our overall approach of systematic dissection of genetic and molecular basis of host susceptibility is not unique to GAS infections, but can be applied to other infectious diseases to develop better diagnostics, design effective therapeutics and predict disease severity based on a set of genetic and soluble biomarkers.