• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Apr 2002; 160(4): 1599–1608.
PMCID: PMC1462047

A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.

Abstract

Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.

Full Text

The Full Text of this article is available as a PDF (121K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Chou SR, Brownell A, Ko MS, Kaplan J. Interferon-gamma receptor polymorphisms determine strain differences in accessibility of activated lymphocyte NK-triggering antigens to recognition by self-reactive NK cells. Cell Immunol. 2000 Mar 15;200(2):88–97. [PubMed]
  • Dansky HM, Charlton SA, Sikes JL, Heath SC, Simantov R, Levin LF, Shu P, Moore KJ, Breslow JL, Smith JD. Genetic background determines the extent of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 1999 Aug;19(8):1960–1968. [PubMed]
  • Dansky HM, Charlton SA, Harper MM, Smith JD. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4642–4646. [PMC free article] [PubMed]
  • De Caterina R, Bourcier T, Laufs U, La Fata V, Lazzerini G, Neish AS, Libby P, Liao JK. Induction of endothelial-leukocyte interaction by interferon-gamma requires coactivation of nuclear factor-kappaB. Arterioscler Thromb Vasc Biol. 2001 Feb;21(2):227–232. [PubMed]
  • Dong ZM, Brown AA, Wagner DD. Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation. 2000 May 16;101(19):2290–2295. [PubMed]
  • Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell. 2001 Feb 23;104(4):503–516. [PubMed]
  • Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998 Aug;2(2):275–281. [PubMed]
  • Gupta S, Pablo AM, Jiang X c, Wang N, Tall AR, Schindler C. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997 Jun 1;99(11):2752–2761. [PMC free article] [PubMed]
  • Hedrick CC, Castellani LW, Warden CH, Puppione DL, Lusis AJ. Influence of mouse apolipoprotein A-II on plasma lipoproteins in transgenic mice. J Biol Chem. 1993 Sep 25;268(27):20676–20682. [PubMed]
  • Hussaini IM, LaMarre J, Lysiak JJ, Karns LR, VandenBerg SR, Gonias SL. Transcriptional regulation of LDL receptor-related protein by IFN-gamma and the antagonistic activity of TGF-beta(1) in the RAW 264.7 macrophage-like cell line. J Leukoc Biol. 1996 May;59(5):733–739. [PubMed]
  • Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. [PubMed]
  • Lander ES, Green P, Abrahamson J, Barlow A, Daly MJ, Lincoln SE, Newberg LA, Newburg L. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics. 1987 Oct;1(2):174–181. [PubMed]
  • Panousis CG, Zuckerman SH. Interferon-gamma induces downregulation of Tangier disease gene (ATP-binding-cassette transporter 1) in macrophage-derived foam cells. Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1565–1571. [PubMed]
  • Li H, Freeman MW, Libby P. Regulation of smooth muscle cell scavenger receptor expression in vivo by atherogenic diets and in vitro by cytokines. J Clin Invest. 1995 Jan;95(1):122–133. [PMC free article] [PubMed]
  • Pitman WA, Hunt MH, McFarland C, Paigen B. Genetic analysis of the difference in diet-induced atherosclerosis between the inbred mouse strains SM/J and NZB/BINJ. Arterioscler Thromb Vasc Biol. 1998 Apr;18(4):615–620. [PubMed]
  • Lincoln SE, Lander ES. Systematic detection of errors in genetic linkage data. Genomics. 1992 Nov;14(3):604–610. [PubMed]
  • Lusis AJ. Atherosclerosis. Nature. 2000 Sep 14;407(6801):233–241. [PMC free article] [PubMed]
  • Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. [PubMed]
  • Machleder D, Ivandic B, Welch C, Castellani L, Reue K, Lusis AJ. Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism. J Clin Invest. 1997 Mar 15;99(6):1406–1419. [PMC free article] [PubMed]
  • Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9607–9611. [PMC free article] [PubMed]
  • Manly KF. A Macintosh program for storage and analysis of experimental genetic mapping data. Mamm Genome. 1993;4(6):303–313. [PubMed]
  • Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med. 1994 Apr 14;330(15):1041–1046. [PubMed]
  • Markel P, Shu P, Ebeling C, Carlson GA, Nagle DL, Smutko JS, Moore KJ. Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat Genet. 1997 Nov;17(3):280–284. [PubMed]
  • Mehrabian M, Wong J, Wang X, Jiang Z, Shi W, Fogelman AM, Lusis AJ. Genetic locus in mice that blocks development of atherosclerosis despite extreme hyperlipidemia. Circ Res. 2001 Jul 20;89(2):125–130. [PubMed]
  • Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. [PubMed]
  • Moore KJ. Utilization of mouse models in the discovery of human disease genes. Drug Discov Today. 1999 Mar;4(3):123–128. [PubMed]
  • Moore KJ, Nagle DL. Complex trait analysis in the mouse: The strengths, the limitations and the promise yet to come. Annu Rev Genet. 2000;34:653–686. [PubMed]
  • Schönbeck U, Mach F, Sukhova GK, Murphy C, Bonnefoy JY, Fabunmi RP, Libby P. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res. 1997 Sep;81(3):448–454. [PubMed]
  • Mu JL, Naggert JK, Svenson KL, Collin GB, Kim JH, McFarland C, Nishina PM, Levine DM, Williams KJ, Paigen B. Quantitative trait loci analysis for the differences in susceptibility to atherosclerosis and diabetes between inbred mouse strains C57BL/6J and C57BLKS/J. J Lipid Res. 1999 Jul;40(7):1328–1335. [PubMed]
  • Selzman CH, Shames BD, Whitehill TA, Harken AH, McIntyre RC., Jr Class II cytokine receptor ligands inhibit human vascular smooth muscle proliferation. Surgery. 1998 Aug;124(2):318–327. [PubMed]
  • Nishina PM, Wang J, Toyofuku W, Kuypers FA, Ishida BY, Paigen B. Atherosclerosis and plasma and liver lipids in nine inbred strains of mice. Lipids. 1993 Jul;28(7):599–605. [PubMed]
  • Smith JD, Breslow JL. The emergence of mouse models of atherosclerosis and their relevance to clinical research. J Intern Med. 1997 Aug;242(2):99–109. [PubMed]
  • Oemar BS, Werner A, Garnier JM, Do DD, Godoy N, Nauck M, März W, Rupp J, Pech M, Lüscher TF. Human connective tissue growth factor is expressed in advanced atherosclerotic lesions. Circulation. 1997 Feb 18;95(4):831–839. [PubMed]
  • Stewart-Phillips JL, Lough J, Skamene E. ATH-3, a new gene for atherosclerosis in the mouse. Clin Invest Med. 1989 Apr;12(2):121–126. [PubMed]
  • van Ree JH, van den Broek WJ, Dahlmans VE, Groot PH, Vidgeon-Hart M, Frants RR, Wieringa B, Havekes LM, Hofker MH. Diet-induced hypercholesterolemia and atherosclerosis in heterozygous apolipoprotein E-deficient mice. Atherosclerosis. 1994 Nov;111(1):25–37. [PubMed]
  • Paigen B, Albee D, Holmes PA, Mitchell D. Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position of Ath-1, a gene determining atherosclerosis susceptibility. Biochem Genet. 1987 Aug;25(7-8):501–511. [PubMed]
  • Welch CL, Bretschger S, Latib N, Bezouevski M, Guo Y, Pleskac N, Liang CP, Barlow C, Dansky H, Breslow JL, et al. Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model. Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7946–7951. [PMC free article] [PubMed]
  • Paigen B, Mitchell D, Holmes PA, Albee D. Genetic analysis of strains C57BL/6J and BALB/cJ for Ath-1, a gene determining atherosclerosis susceptibility in mice. Biochem Genet. 1987 Dec;25(11-12):881–892. [PubMed]
  • Weng W, Breslow JL. Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14788–14794. [PMC free article] [PubMed]
  • Paigen B, Mitchell D, Reue K, Morrow A, Lusis AJ, LeBoeuf RC. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3763–3767. [PMC free article] [PubMed]
  • Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein E alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol. 1996 Oct;16(10):1250–1255. [PubMed]
  • Paigen B, Nesbitt MN, Mitchell D, Albee D, LeBoeuf RC. Ath-2, a second gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Genetics. 1989 May;122(1):163–168. [PMC free article] [PubMed]
  • Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992 Oct 16;258(5081):468–471. [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...