Cypr8b^DBA/2J
QTL Variant Detail

Summary

• QTL variant: Cypr8b^DBA/2J
• Name: cytokine production 8b; DBA/2J
• MGI ID: MGI:5818827
• QTL: Cypr8b Location: unknown Genetic Position: Chr6, Syntenic

Variant origin

• Strain of Specimen: BXD

Variant description

• Allele Type: QTL
• Inheritance: Not Specified

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:221202

Severe respiratory and systemic disease caused by human infection with avian H5N1 influenza virus is characterized by high viral load and increased production of proinflammatory cytokines, which, if left untreated, often results in death. To identify variant host genes associated with increased virus replication and severe influenza disease, the authors performed a QTL analysis on pro-inflammatory cytokine production 48 hours after intranasal infection with highly pathogenic H5N1 influenza virus.

Pro-inflammatory cytokines CCL2, TNF-alpha, and IFN-alpha, were measured by ELISA in lung homogenates of DBA/2J, C57BL/6J, and 44 different BXD recombinant inbred (RI) mouse strains. Virus titer was also assessed in a subset of these animals.

CCL2 (8-fold), TNF-alpha (24-fold) and IFN-alpha (8-fold) concentrations varied significantly among the different BXD RI strains. Cytokine concentration correlated very well (r = 0.86-0.96, P <0.0001) with virus titer suggesting that early cytokine production is due to increased virus infection and replication.

Linkage analysis of cytokine concentration revealed a significant locus on Chromosome 6 associated with differences in TNF-alpha, IFN-alpha, and CCL2 cytokine concentration (LOD = 5.64). This locus, named Cypr8 (cytokine production 8), accounted for approximately 18% of the observed phenotypic variation in the BXD population studied, and the DBA/2J allele increased the trait value.

Three sub-QTL corresponding to concentration of specific cytokines after infection with HK213 virus were identified within the Cypr8 QTL:

Cypr8a (cytokine production 8a) is significant for increased CCL2 concentration and is located on Chromosome 6 from 3.4 - 14.5 Mb with a peak LOD score of 3.69 (LRS = 17).

Cypr8b (cytokine production 8b) is significant for increased TNF-alpha concentration and is located on Chromosome 6 from 3.4 - 14.5 Mb with a peak LOD score of 5.42 (LRS = 25).

Cypr8c (cytokine production 8c) is significant for increased INF-alpha concentration and is located on Chromosome 6 from 3.4 - 14.5 Mb with a peak LOD score of 5.86 (LRS = 27).

TNF-alpha concentrations also associated significantly with a locus on Chromosome 1 which we have named Cypr9 (cytokine production 9). The Cypr9 locus is between 154.5 and 160.6 Mb with a peak LOD score of 3.69 (peak LRS = 17).

Sequence and RNA expression analysis of the Cypr8 locus identified several candidate host genes containing missense mutations or deletions; Samd9l, Ica1, and Slc25a13. To study the role of Slc25a13, the authors obtained a Slc25a13 knockout line of mice bred onto the BALB/cAnN background, but upon challenge with H5N1 influenza virus observed no effect on CCL2 production, or morbidity and mortality.

References

• Original: J:221202 Boon AC, et al., A novel genetic locus linked to pro-inflammatory cytokines after virulent H5N1 virus infection in mice. BMC Genomics. 2014;15:1017
• All: 1 reference(s)