Genetic analysis of a mouse cross implicates an anti-inflammatory gene in control of atherosclerosis susceptibility

Nearly all genetic crosses generated from Apoe^-/- or Lldlr^-/- mice for genetic analysis of atherosclerosis have used C57BL/6 J (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 non-synonymous 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.