title: Genetic analysis of a mouse cross implicates an anti-inflammatory gene in control of atherosclerosis susceptibility.
abstract: 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 F2mice were generated from the two Apoe-/-strains to perform quantitative trait locus (QTL) analysis of atherosclerosis. F2mice 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.
authors.affiliation: Departments of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Garrett
authors.affiliation: Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Grainger
authors.affiliation: Departments of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Chen
authors.affiliation: Departments of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA. ws4v@virginia.edu.|Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA. ws4v@virginia.edu.|University of Virginia, Snyder Bldg Rm 266, 480 Ray C. Hunt Dr, P.O. Box 801339, Fontaine Research Park, Charlottesville, VA, 22908, USA. ws4v@virginia.edu.
authors.forename: Weibin
authors.initials: W
authors.lastname: Shi
mesh_terms: D000483:Alleles; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D066273:Diet, Western / Q000009:adverse effects; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D016678:Genome; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D011973:Receptors, LDL / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; C513261:Tnfaip3 protein, mouse