No abstract

Nearly all genetic crosses generated from Apoe−/− or Lldlr−/− mice for genetic analysis of atherosclerosis have used C57BL/6J (B6) mice as one parental strain; thus limiting their mapping power and coverage of allelic diversity. SM/J-Apoe−/− and BALB/cJ-Apoe−/− mice differ significantly in atherosclerosis susceptibility. 224 male F2 mice were generated from the two Apoe−/− strains to perform quantitative trait locus (QTL) analysis of atherosclerosis. F2 mice were fed 5 weeks of Western diet and analyzed for atherosclerotic lesions in the aortic root. Genome-wide scans with 144 informative SNP markers identified a significant locus near 20.2 Mb on chromosome 10 (LOD score: 6.03), named Ath48, and a suggestive locus near 49.5 Mb on chromosome 9 (LOD: 2.29; Ath29) affecting atherosclerotic lesion sizes. Using bioinformatics tools, we prioritized 12 candidate genes for Ath48. Of them, Tnfaip3, an anti-inflammatory gene, is located precisely underneath the linkage peak and contains two nonsynonymous SNPs leading to conservative amino acid substitutions. Thus, this study demonstrates the power of forward genetics involving the use of a different susceptible strain and bioinformatics tools in finding atherosclerosis susceptibility genes.

No abstract