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

Mamm Genome. 2017 Apr;28(3-4):90-99. doi: 10.1007/s00335-016-9677-0. Epub 2017 Jan 23.

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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Aorta / pathology
  • Apolipoproteins E / genetics*
  • Atherosclerosis / genetics*
  • Atherosclerosis / pathology
  • Chromosome Mapping
  • Crosses, Genetic
  • Diet, Western / adverse effects
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Genome
  • Humans
  • Inflammation / genetics*
  • Inflammation / pathology
  • Mice
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci / genetics*
  • Receptors, LDL / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3 / genetics*

Substances

  • Apolipoproteins E
  • Receptors, LDL
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Tnfaip3 protein, mouse