Artles^CAST/EiJ
QTL Variant Detail

Summary

• QTL variant: Artles^CAST/EiJ
• Name: arterial lesions; CAST/EiJ
• MGI ID: MGI:2156399
• QTL: Artles Location: unknown Genetic Position: Chr6, Syntenic

Variant origin

• Strain of Specimen: CAST/EiJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers resistance to arterial lesions and decreased plasma insulin levels compared to C57BL/6J. (J:70961)
• Inheritance: Codominant

Expression

In Structures Affected by this Mutation:

2 anatomical structure(s)

Notes

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

J:70961

Genome scan at an average marker density of 10 cM was performed on approximately 250 (CAST/Ei x C57BL/6J)F2 animals to identify QTLs associated with arterial lesion formation. Animals were places on a 15 week atherogenic diet at 4 months of age. Parental strain CAST/Ei is resistant to atherosclerosis when placed on an atherogenic diet whereas parental strain C57BL/6J is susceptible. A significant QTL associated with arterial lesion formation and insulin level, Artles, mapped to approximately 61 cM on mouse Chromosome 6 with a maximum LOD score 6.7 near D6Mit256. Artles spans an interval of 38.5 cM - 67 cM and appears to be inherited in a codominant fashion. Artles was confirmed in congenic strains carrying CAST/Ei-derived DNA spanning 38.5 cM - 67 cM ofmouse Chromosome 6 (D6Mit102 to D6Mit198) on a C57BL/6J background. The congenics exhibited similar resistance to arterial lesions as donor strain CAST/Ei. The same protective effect was observed in a congenic strain carrying the same CAST/Ei-derived region (38.5 cM-67 cM of mouse Chromosome 6) on a highly susceptible LDLR -/- background. Possible candidate genes in the region of Artles include Pparg and Apobec1.

J:109792

Previously identified arterial lesion susceptibility QTL Artles (arterial lesions) mapped to 61 cM on mouse Chromosome 6. This locus was refined into 2 separate QTL designated Ath37 and Ath38 using 16 different interval specific congenic strains derived from B6.CAST-(D6Mit102-D6Mit198) Ldlr^tm1Her, also referred to as CON6. At 12 weeks of age, female animals were placed on a Western high fat diet for a duration of 8 weeks.

The proximal locus Ath37 spans a 12.1 Mb interval between D6Mit115 (51 cM) and D6Mit61 (62.3 cM). Adipor2 (60.7 cM), A2m (61.7 cM), and Cd163 are potential candidate genes mapping near Ath37. The distal locus Ath38 spans a 7.8 Mb interval between D6Mit61 (62.3 cM) and D6Mit258 (65.5 cM). Olr1 is a potential candidate gene for Ath38. CAST/Ei-derived alleles at Ath37 and Ath38 confer reduced atherosclerotic lesion size on a high fat diet by 43% and 41%, respectively. These loci may interact epistatically.

A 13.1 Mb region on the telomeric end of chromosome 6 also shows evidence for harboring at least 2 other genes involved in susceptibility to atherosclerotic lesions. The 2 genes appear to have opposite effects, where CAST/Ei-derived alleles at one confers protection and CAST/Ei-derived alleles at the other confers susceptibility.

Alox5 (53.2 cM), a candidate gene for Artles, maps proximal to both Ath37 and Ath38. Animals homozygous for the Alox5^tm1Fun knockout allele exhibit 10-fold reduced atherosclerosis on a high fat diet compared to C57BL/6J controls. However, homozygosity for CAST/Ei Alox5 alleles does not decrease the frequency of aortic aneurysms as hypothesized.

References

• Original: J:70961 Mehrabian M, et al., Genetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia. Circ Res. 2001 Jul 20;89(2):125-30
• All: 2 reference(s)