Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  7
• Reference
  J:175065 Vorraro F, et al., Genetic control of IL-1 beta production and inflammatory response by the mouse Irm1 locus. J Immunol. 2010 Aug 1;185(3):1616-21
• ID
  MGI:5806332

Genes

Gene	Assay Type
Irm1	visible phenotype

Notes

• Experiment
  Genetic control of acute inflammatory response (AIR) was studied using AIRmax and AIRmin mouse lines, phenotypically selected based on their respectively high and low responses to acute inflammation.
  
  The AIR phenotype was determined by quantifiying the number of inflitrating cells in the 24-h exudate induced by Biogel P-100 s.c.injection and by ex-vivo IL-1Beta production by leukocytes stimulated with LPS and ATP. AIRmax and AIRmin mice displayed a 30-fold difference in the number of infiltrating leukocytes of Biogel-induced inflammatory exudates.
  
  To map the QTL responsible for the different phenotypes a genome-wide scan with single nucleotide polymorphism (SNP) arrays of (AIRmax x AIRmin)F2 intercrossed mice (290) was carried out.
  
  A genome-wide scan of the autosomes, with the additive model and sex as an additive covariate, detected a statistically significant linkage bewteen Chromosome 7 markers and the number of infiltrated cells phenotype with a LOD score of 3.61. The QTL peak mapped at 130.75 Mb near rs6275579 with a 1-LOD confidence interval from 116.75 to 139.75 Mb. Association analysis at markers located within the interval pointed to rs13479477 (124.38 Mb) and to rs32381191 (135.55.Mb) as the best associated markers respectively. Both markers displayed a clear allele-dosage effect on the number of infiltrated cells phenotype.
  
  A QTL linked to IL-1Beta production with a LOD score of 9.35 also mapped to Chromosome 7 at 137.75 Mb near SNP rs13479535. With a 1-LOD confidence interval from 130.75 to 144.75 Mb the QTL consequently overlapped with the QTL detected for the infiltrated cells phenotype. Within the interval the markers showing the best statistical associations were SNP rs32381191 and SNP rs31680975. Both markers also displayed a clear allele-dosage effect on the IL-1Beta production phenotype.
  
  The QTL, spanning both phenotypes was designated Irm1, inflammatory response modulator 1.
  The 1-LOD confidence intervals of the QTL for inflammatory response and IL-1B production overlap in a region that extends from 130.75 to 144.75 Mb on Chromosome 7. The width and the shape of the QTL suggest that the Irm1 locus may result from two or more closely related QTL but fine mapping of the Irm1 locus is needed to claify the point.
  
  To characterize the origin of the Irm1 locus from the eight founder inbred strains allelic association in the originating AIRmax and AIRmin lines was performed. Then genotype data of the same SNPs from the eight inbred strains were used to perform haplotype analysis. The analysis failed to identify any shared haplotype blocks. The identification of the ancestral haplotype associated with the Irm1 locus and of the inbred strains transmitting either the susceptible or resistant Irm1 alleles to AIR lines awaits fine-mapping of the region.
  
  The Pycard gene, which mediates the inflammatory response and apoptotic signaling pathways via the activation of caspases maps at app 135.13 Mb. Sequencing of the Pycard gene revealed that the sequence was identical in the AIR lines, except for SNPs rs51540238 and rs31684669 situated in the 3' region and in the first intron respectively, of Pycard. Although both were polymorphic, the alleles were similarly distributed in the AIRmax and AIRmin mice, suggesting that variations within the Pycard gene do not account for the different ability of the two mouse lines to produce IL-1Beta.