Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1987 Jun;84(11):3763–3767. doi: 10.1073/pnas.84.11.3763

Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice.

B Paigen, D Mitchell, K Reue, A Morrow, A J Lusis, R C LeBoeuf
PMCID: PMC304956  PMID: 3473481

Abstract

High density lipoprotein (HDL) is the major plasma lipoprotein found in mice fed normal laboratory chow containing 4% fat. When female mice from some inbred strains, such as C57BL/6, are fed a high fat diet (1.25% cholesterol, 15% fat, and 0.5% cholic acid), the levels of HDL-cholesterol decrease by about 50%, and lipid staining lesions form in the aorta within 14 weeks. In other strains of mice, such as C3H and BALB/c, HDL-lipid levels decrease only slightly, and few or no aortic lesions are observed at 14 weeks. The genetic basis of these phenotypic differences was analyzed by using recombinant inbred strains derived from C57BL/6 and BALB/c and also from C57BL/6 and C3H/He. The two phenotypes segregated as simple Mendelian traits, and no recombination was observed between them. Thus, HDL-cholesterol levels and susceptibility to atherosclerosis appear to be determined by the same gene (or by two closely linked genetic factors that are a maximum of 1.7 centimorgans apart). This gene was named Ath-1, for atherosclerosis susceptibility, with alleles r for resistance and s for susceptibility. Ath-1 maps on chromosome 1 near Alp-2, a gene that determines the structure of apolipoprotein A-II, one of the two major proteins found in HDL. Ath-1 is clearly separable from Alp-2, and the distance between these genes is 6.0 centimorgans with a standard error of 4.2 centimorgans. In humans, levels of HDL are inherited and are inversely correlated with atherosclerosis; familial hyperalphalipoproteinemia is associated with high levels of HDL-cholesterol and decreased risk of heart disease. The human trait phenotypically resembles Ath-1 in the mouse.

Full text

PDF
3763

Images in this article

3764Image
on p.3764

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Breckenridge W. C., Roberts A., Kuksis A. Lipoprotein levels in genetically selected mice with increased susceptibility to atherosclerosis. Arteriosclerosis. 1985 May-Jun;5(3):256–264. doi: 10.1161/01.atv.5.3.256. [DOI] [PubMed] [Google Scholar]
  2. Burstein M., Scholnick H. R., Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970 Nov;11(6):583–595. [PubMed] [Google Scholar]
  3. Elliott R. W., Romejko C., Hohman C. Mapping the gene for LTW-4, a 26,000 molecular weight major protein of mouse liver and kidney. Mol Gen Genet. 1980;180(1):17–22. doi: 10.1007/BF00267347. [DOI] [PubMed] [Google Scholar]
  4. Glueck C. J., Gartside P., Fallat R. W., Sielski J., Steiner P. M. Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med. 1976 Dec;88(6):941–957. [PubMed] [Google Scholar]
  5. Gordon T., Castelli W. P., Hjortland M. C., Kannel W. B., Dawber T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707–714. doi: 10.1016/0002-9343(77)90874-9. [DOI] [PubMed] [Google Scholar]
  6. Izzo C., Grillo F., Murador E. Improved method for determination of high-density-lipoprotein cholesterol I. Isolation of high-density lipoproteins by use of polyethylene glycol 6000. Clin Chem. 1981 Mar;27(3):371–374. [PubMed] [Google Scholar]
  7. Kannel W. B., Castelli W. P., Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham study. Ann Intern Med. 1979 Jan;90(1):85–91. doi: 10.7326/0003-4819-90-1-85. [DOI] [PubMed] [Google Scholar]
  8. Knott T. J., Eddy R. L., Robertson M. E., Priestley L. M., Scott J., Shows T. B. Chromosomal localization of the human apoprotein CI gene and of a polymorphic apoprotein AII gene. Biochem Biophys Res Commun. 1984 Nov 30;125(1):299–306. doi: 10.1016/s0006-291x(84)80368-x. [DOI] [PubMed] [Google Scholar]
  9. LeBoeuf R. C., Puppione D. L., Schumaker V. N., Lusis A. J. Genetic control of lipid transport in mice. I. Structural properties and polymorphisms of plasma lipoproteins. J Biol Chem. 1983 Apr 25;258(8):5063–5070. [PubMed] [Google Scholar]
  10. Lusis A. J., Taylor B. A., Wangenstein R. W., LeBoeuf R. C. Genetic control of lipid transport in mice. II. Genes controlling structure of high density lipoproteins. J Biol Chem. 1983 Apr 25;258(8):5071–5078. [PubMed] [Google Scholar]
  11. Mathieson B. J., Sharrow S. O., Bottomly K., Fowlkes B. J. Ly 9, an alloantigenic marker of lymphocyte differentiation. J Immunol. 1980 Nov;125(5):2127–2136. [PubMed] [Google Scholar]
  12. Noble R. P., Hatch F. T., Mazrimas J. A., Lindgren F. T., Jensen L. C., Adamson G. L. Comparison of lipoprotein analysis by agarose gel and paper electrophoresis with analytical ultracentrifugation. Lipids. 1969 Jan;4(1):55–59. doi: 10.1007/BF02531795. [DOI] [PubMed] [Google Scholar]
  13. Oram J. F., Albers J. J., Cheung M. C., Bierman E. L. The effects of subfractions of high density lipoprotein on cholesterol efflux from cultured fibroblasts. Regulation of low density lipoprotein receptor activity. J Biol Chem. 1981 Aug 25;256(16):8348–8356. [PubMed] [Google Scholar]
  14. Paigen B., Havens M. B., Morrow A. Effect of 3-methylcholanthrene on the development of aortic lesions in mice. Cancer Res. 1985 Aug;45(8):3850–3855. [PubMed] [Google Scholar]
  15. Paigen B., Morrow A., Brandon C., Mitchell D., Holmes P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis. 1985 Oct;57(1):65–73. doi: 10.1016/0021-9150(85)90138-8. [DOI] [PubMed] [Google Scholar]
  16. Roberts A., Thompson J. S. Genetic factors in the development of atheroma and on serum total cholesterol levels in inbred mice and their hybrids. Prog Biochem Pharmacol. 1977;13:298–305. [PubMed] [Google Scholar]
  17. Rudel L. L., Morris M. D. Determination of cholesterol using o-phthalaldehyde. J Lipid Res. 1973 May;14(3):364–366. [PubMed] [Google Scholar]
  18. Saito F. A pedigree of homozygous familial hyperalphalipoproteinemia. Metabolism. 1984 Jul;33(7):629–633. doi: 10.1016/0026-0495(84)90061-1. [DOI] [PubMed] [Google Scholar]
  19. Scott J., Knott T. J., Priestley L. M., Robertson M. E., Mann D. V., Kostner G., Miller G. J., Miller N. E. High-density lipoprotein composition is altered by a common DNA polymorphism adjacent to apoprotein AII gene in man. Lancet. 1985 Apr 6;1(8432):771–773. doi: 10.1016/s0140-6736(85)91443-6. [DOI] [PubMed] [Google Scholar]
  20. Tall A. R., Small D. M. Body cholesterol removal: role of plasma high-density lipoproteins. Adv Lipid Res. 1980;17:1–51. [PubMed] [Google Scholar]
  21. Wilcox F. H., Hirschhorn L., Taylor B. A., Womack J. E., Roderick T. H. Genetic variation in alkaline phosphatase of the house mouse (Mus musculus) with emphasis on a manganese-requiring isozyme. Biochem Genet. 1979 Dec;17(11-12):1093–1107. doi: 10.1007/BF00504347. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES