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

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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.

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Acknowledgements

This work was supported by NIH grants DK097120 and HL112281.

Author contributions

ENG sectioned samples and quantitated atherosclerotic lesions. ATG analyzed the data. JL analyzed candidate gene expression. MHC supervised morphometric analysis of atherosclerotic lesions. WS constructed the cross, collected samples, and supervised the study. All authors read and edited the manuscript.

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Authors and Affiliations

  1. Departments of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA, USA

    Norman E. Garrett III, Jing Li, Mei-Hua Chen & Weibin Shi

  2. Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA, USA

    Andrew T. Grainger & Weibin Shi

  3. University of Virginia, Snyder Bldg Rm 266, 480 Ray C. Hunt Dr, P.O. Box 801339, Fontaine Research Park, Charlottesville, VA, 22908, USA

    Weibin Shi

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  1. Norman E. Garrett III
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Garrett, N.E., Grainger, A.T., Li, J. et al. Genetic analysis of a mouse cross implicates an anti-inflammatory gene in control of atherosclerosis susceptibility. Mamm Genome 28, 90–99 (2017). https://doi.org/10.1007/s00335-016-9677-0

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