Ath8^NZB/BlNJ
QTL Variant Detail

Summary

• QTL variant: Ath8^NZB/BlNJ
• Name: atherosclerosis 8; NZB/BlNJ
• MGI ID: MGI:3528303
• QTL: Ath8 Location: Chr4:45658442-105156995 bp Genetic Position: Chr4, cM position of peak correlated region/allele: 24.16 cM
• QTL Note: genome coordinates based on the boundaries of the QTL region

Variant origin

• Strain of Specimen: NZB/BlNJ

Variant description

• Allele Type: QTL
• Inheritance: Dominant

Notes

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

J:94346

Genome scan was performed on female animals from a (SM/J x NZB/BlNJ)F1 x SM/J backcross to identify QTLs associated with susceptibility to atherosclerosis. Female animals from parental strain SM/J develop large atherosclerotic lesions when placed on a high fat diet whereas female animals from parental strain NZB/BlNJ develop small lesions. 65 microsatellite markers were typed in 20 backcross mice with the largest lesions and 20 backcross mice with no lesions. A locus showing suggestive linkage to lesion size was detected on mouse Chromosome 4 near D4Mit44 (LOD=2.7). This locus was confirmed by genotyping 21 markers across chromosome 4 in 258 female (SM/J x NZB/BlNJ)F2 intercross animals and is named Ath8 (atherosclerosis 8). SM/J-derived alleles at Ath8 confer increased lesion size with a recessive mode of inheritance. Peak linkage occurred at D4Mit44 (LOD=3.6) and the confidence interval extends 23 cM. Ath8 is flanked by D4Mit214 (18 cM) and D4Mit306 (51 cM). There are 2 peaks under the LOD plot for this interval so it is possible that more than 1 QTL may exist in this region.

Potential candidate genes for Ath8 are Tlr4 (33 cM), Cyp2j5 (46.5 cM), and Angptl3 (49.3 cM). Sequence analysis of Tlr4 revealed an SNP in exon 3 between SM/J and NZB/BlNJ that does not result in an amino acid change. Sequence analysis of Cyp2j5 did not reveal any polymorphisms but real-time PCR showed higher liver expression in NZB/BlNJ animals on a CHOW diet compared to SM/J. No expression difference was observed on the high fat diet. Sequence analysis of Angptl3 revealed 1 conservative and 1 non-conservative (Q233G) change in the linker domain of exon 3 and 1 non-conservative change (Y250F) in the fibrinogen homology domain of exon 4 between NZB/BlNJ and SM/J. Analysis of 8 other inbred strains showed the Angptl3 sequence to be identical to NZB/BlNJ inferring that the SM/J allele is the variant. No gene expression difference was observed between NZB/BlNJ and SM/J. Interestingly, 2 SNPs in the promoter region of ANGPTL3 showedlinkage to atherosclerotic lesion size, plasma triglycerides, and VLDL lipids in human studies.

References

• Original: J:94346 Korstanje R, et al., Locating Ath8, a locus for murine atherosclerosis susceptibility and testing several of its candidate genes in mice and humans. Atherosclerosis. 2004 Dec;177(2):443-50
• All: 1 reference(s)