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

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 RW, Kotb M - PLoS Pathog. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Mid-South Center for Biodefense and Security, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

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.

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Related in: MedlinePlus

Recombinant inbred BXD strain distribution patterns at region of interest on Chr 2.(A) Haplotype maps of the first QTL on Chr 2 between 20–34 Mb showing available BXD strains. Haplotype maps were used for in silico selection of strains for survival studies based on the strain distribution patterns, where B allele (blue bars) inherited from the resistant parent C57Bl/6J and D alleles form the susceptible parent DBA/2J, beige bars indicate strains that are heterozygous at this region, resembling an F1. Arrows indicate BXD strains 34, 51, 60, 64, 79, 94, and 100. (B) Haplotype maps of the first QTL region on Chr 2 between 20—34 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. Resistant strains show a pattern of accumulation of alleles inherited from resistant parent (B) C57Bl/6J (blue bars) while the susceptible strains show a pattern of alleles from susceptible parent (D) DBA/2J (red bars), with the exception of BXD94 strain, heterozygous (beige bars) at the QTL region. (C) Haplotype maps of the second QTL region on Chr 2 between 125—150 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. BXD genotype data set can be downloaded from www.genenetwork.org/genotypes/BXD.geno.
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ppat-1000042-g003: Recombinant inbred BXD strain distribution patterns at region of interest on Chr 2.(A) Haplotype maps of the first QTL on Chr 2 between 20–34 Mb showing available BXD strains. Haplotype maps were used for in silico selection of strains for survival studies based on the strain distribution patterns, where B allele (blue bars) inherited from the resistant parent C57Bl/6J and D alleles form the susceptible parent DBA/2J, beige bars indicate strains that are heterozygous at this region, resembling an F1. Arrows indicate BXD strains 34, 51, 60, 64, 79, 94, and 100. (B) Haplotype maps of the first QTL region on Chr 2 between 20—34 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. Resistant strains show a pattern of accumulation of alleles inherited from resistant parent (B) C57Bl/6J (blue bars) while the susceptible strains show a pattern of alleles from susceptible parent (D) DBA/2J (red bars), with the exception of BXD94 strain, heterozygous (beige bars) at the QTL region. (C) Haplotype maps of the second QTL region on Chr 2 between 125—150 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. BXD genotype data set can be downloaded from www.genenetwork.org/genotypes/BXD.geno.

Mentions: Our mapped QTLs directed us to select more strains for survival experiments based on differences in their haplotypes within the QTLs. For example, we selected BXD100 with a D haplotype at Chr 2 between 22–34 Mb region, Figure 3A, and found it to be susceptible. Similarly, we tested BXD87 with a B haplotype in the same region and this strain as predicted, exhibited a resistant phenotype. To further narrow down the mapped QTLs, we chose strains with breakage in the mapped interval, i.e. with recombination at Chr 2 region 22–34 Mb for further survival testing (Figure 3A). BXD34 with a B haplotype at Chr 2 between 24–33.15 Mb region, was resistant, while BXD60 with a B haplotype at Chr 2 between 20–23.27 Mb region, was susceptible, Figure 1A and 3A. This narrowed down the relevant susceptibility region to Chr 2 between 23.27–33.15 Mb. Using more strains with recombination at this narrowed region, we found BXD51, 64, and 79 to be quite interesting as they showed intermediate resistance suggesting that genes at this region are candidate modulators of the mapped QTL, Figure 3B. Another interesting strain was BXD94 that we found susceptible to infection, yet has a heterozygous genotyping, suggesting that D allele exhibited dominance, Figure 3B.


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

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 RW, Kotb M - PLoS Pathog. (2008)

Recombinant inbred BXD strain distribution patterns at region of interest on Chr 2.(A) Haplotype maps of the first QTL on Chr 2 between 20–34 Mb showing available BXD strains. Haplotype maps were used for in silico selection of strains for survival studies based on the strain distribution patterns, where B allele (blue bars) inherited from the resistant parent C57Bl/6J and D alleles form the susceptible parent DBA/2J, beige bars indicate strains that are heterozygous at this region, resembling an F1. Arrows indicate BXD strains 34, 51, 60, 64, 79, 94, and 100. (B) Haplotype maps of the first QTL region on Chr 2 between 20—34 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. Resistant strains show a pattern of accumulation of alleles inherited from resistant parent (B) C57Bl/6J (blue bars) while the susceptible strains show a pattern of alleles from susceptible parent (D) DBA/2J (red bars), with the exception of BXD94 strain, heterozygous (beige bars) at the QTL region. (C) Haplotype maps of the second QTL region on Chr 2 between 125—150 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. BXD genotype data set can be downloaded from www.genenetwork.org/genotypes/BXD.geno.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2277464&req=5

ppat-1000042-g003: Recombinant inbred BXD strain distribution patterns at region of interest on Chr 2.(A) Haplotype maps of the first QTL on Chr 2 between 20–34 Mb showing available BXD strains. Haplotype maps were used for in silico selection of strains for survival studies based on the strain distribution patterns, where B allele (blue bars) inherited from the resistant parent C57Bl/6J and D alleles form the susceptible parent DBA/2J, beige bars indicate strains that are heterozygous at this region, resembling an F1. Arrows indicate BXD strains 34, 51, 60, 64, 79, 94, and 100. (B) Haplotype maps of the first QTL region on Chr 2 between 20—34 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. Resistant strains show a pattern of accumulation of alleles inherited from resistant parent (B) C57Bl/6J (blue bars) while the susceptible strains show a pattern of alleles from susceptible parent (D) DBA/2J (red bars), with the exception of BXD94 strain, heterozygous (beige bars) at the QTL region. (C) Haplotype maps of the second QTL region on Chr 2 between 125—150 Mb across BXD strains used in the population-based survival experiments showing the pattern of alleles inherited from each parent at region of interest on Chr 2. The different BXD strains are rank-ordered according to their susceptibility to GAS sepsis form susceptible to more resistant. BXD genotype data set can be downloaded from www.genenetwork.org/genotypes/BXD.geno.
Mentions: Our mapped QTLs directed us to select more strains for survival experiments based on differences in their haplotypes within the QTLs. For example, we selected BXD100 with a D haplotype at Chr 2 between 22–34 Mb region, Figure 3A, and found it to be susceptible. Similarly, we tested BXD87 with a B haplotype in the same region and this strain as predicted, exhibited a resistant phenotype. To further narrow down the mapped QTLs, we chose strains with breakage in the mapped interval, i.e. with recombination at Chr 2 region 22–34 Mb for further survival testing (Figure 3A). BXD34 with a B haplotype at Chr 2 between 24–33.15 Mb region, was resistant, while BXD60 with a B haplotype at Chr 2 between 20–23.27 Mb region, was susceptible, Figure 1A and 3A. This narrowed down the relevant susceptibility region to Chr 2 between 23.27–33.15 Mb. Using more strains with recombination at this narrowed region, we found BXD51, 64, and 79 to be quite interesting as they showed intermediate resistance suggesting that genes at this region are candidate modulators of the mapped QTL, Figure 3B. Another interesting strain was BXD94 that we found susceptible to infection, yet has a heterozygous genotyping, suggesting that D allele exhibited dominance, Figure 3B.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Mid-South Center for Biodefense and Security, The University of Tennessee Health Science Center, Memphis, Tennessee, United States of America.

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.

Show MeSH
Related in: MedlinePlus