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Major Gene and Environmental Determinants of High-Density Lipoprotein Cholesterol

Relationship to Atherosclerosis
  • Charles J. Glueck
  • Ingrid Borecki
  • D. C. Rao
  • Peter Laskarzewski
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)

Abstract

Since high-density lipoprotein cholesterol (HDL-C) levels are a major independent risk factor for coronary heart disease, the association of major genes with familial aggregation of both high and low HDL-C emphasizes the importance of heritability for HDL-C in relationship to coronary heart disease. Complex segregation analysis using the unified mixed model in white families from the Collaborative Lipid Research Clinics Family Study cohort was carried out to delineate the mode of familial transmission of plasma HDL-C. Two major HDL-C clusters were identified with means separated by three standard deviation units. For low HDL-C segregating in families, there was significant evidence for a recessive major gene, and there was also evidence of significant multifactorial transmission. The major gene and multifactorial components accounted for 8% and 45% of the total variation of HDL-C levels, whereas the gene frequency for low HDL-C was estimated to be 8% to 9% at the major locus. Separately, segregation analysis was performed on 14 informative nuclear families referred because of early coronary heart disease or stroke and gave clear evidence of a major gene contributing to the etiology of primary depression of HDL-C., with support for a dominant model. Recently, a DNA restriction length polymorphism has been described in the apo A-I, apo C-III, apo A-IV gene complex following PST-1 digestion. The allele frequency of this polymorphism was 2% in control subjects and 67% in index cases of kindreds with familial hypoalphalipoproteinemia. Bottom-decile HDL-C was present in 73% of subjects who were heterozygous or homozygous for the polymorphism. This polymorphism appears to be associated with one of the causes of genetic HDL deficiency that results in premature coronary artery disease. Since the common PST-1 polymorphism is associated with familial hypoalphalipoproteinemia, premature coronary artery disease, and stroke, the observation of a single major locus for low HDL-C has considerable importance. Whether familial hypoalphalipoproteinemia reflects an abnormality of the HDL regulator gene on chromosome 1, the apo A-II gene on chromosome 1, the apo A-I gene on chromosome 11, or perhaps a linkage between the regulator gene and the gene for apo A-I remains to be determined.

Keywords

Major Gene Major Locus Premature Coronary Artery Disease Lipid Research Clinic Premature Coronary Heart Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Borecki, I. B., Rao, D. C., Third, J. H. L. C., Laskarzewski, P., and Glueck, C. J., 1986, A major gene for familial hypoalphalipoproteinemia, Am. J. Hum. Genet. 38:373–381.PubMedGoogle Scholar
  2. Byard, P. J., Glueck, C. J., Borecki, I. B., Laskarzewski, P. M., Third, J. H. L. C., and Rao, D. C., 1984, A genetic study of hypoalphalipoproteinemia, Genet. Epidemiol. 1:43–51.PubMedCrossRefGoogle Scholar
  3. Glueck, C. J., Fallat, R. W., Millett, F., and Steiner, P. M., 1975, Familial hyperalpha-lipoproteinemia, Arch. Intern. Med. 135:1025–1028.PubMedCrossRefGoogle Scholar
  4. Glueck, C. J., Gartside, P., Fallat, R. W., Sielski, J., and Steiner, P. M., 1976, Longevity syndromes: Familial hypobeta and familial hyperalphalipoproteinemia, J. Lab. Clin. Med. 88:941–957.PubMedGoogle Scholar
  5. Glueck, C. J., Gartside, P. S., Tsang, R. C., Mellies, M. J., and Steiner, P. M., 1977, Neonatal familial hyperalpha-lipoproteinemia (preliminary report), Metabolism 26:469–472.PubMedCrossRefGoogle Scholar
  6. Glueck, C. J., Kelly, K., Mellies, M. J., Gartside, P. S., and Steiner, P. M., 1978, Hypercholesterolemia and hyperalpha-lipoproteinemia in school children, Pediatrics 62:478–483.PubMedGoogle Scholar
  7. Glueck, C. J., Daniels, S. R., Bates, S., Benton, C., Tracy, T., and Third, J. C., 1982, Pediatric victims of unexplained stroke and their families: Familial lipid and lipoprotein abnormalities, Pediatrics 69:308–316.PubMedGoogle Scholar
  8. Glueck, C. J., Laskarzewski, P., Rao, D. C., and Morrison, J. A., 1985, Familial aggregations of coronary risk factors, in: Coronary Heart Disease (W. Connor and D. Bristow, eds.), J. B. Lippincott, Philadelphia, pp. 173–193.Google Scholar
  9. Hasstedt, S. J., Ash, K. O., and Williams, R. R., 1986, A re-examination of major locus hypotheses for high density lipoprotein cholesterol level using 2, 170 persons screened in 55 Utah pedigrees, Am. J. Med. Genet. 24:57–67.CrossRefGoogle Scholar
  10. Heuch, I., Namboodiri, K. K., Green, P. P., Kaplan, E. B., Laskarzewski, P., Glueck, C. J., and Elston, R. C., 1985, A multivariate analysis of familial associations of lipoprotein levels in the Lipid Research Clinics Collaborative Family Study: I. Familial correlation and regression analyses, Genet. Epidemiol. 2:283–300.PubMedCrossRefGoogle Scholar
  11. Laskarzewski, P. M., Khoury, P., Kelly, K., Mellies, M. J., Morrison, J. A., and Glueck, C. J., 1982a, Prevalence of familial hyper-and hypolipoproteinemias in blacks-the Princeton School District Study, Prev. Med. 11:142–161.PubMedCrossRefGoogle Scholar
  12. Laskarzewski, P. M., Khoury, P., Morrison, J. A., Kelly, K., Mellies, M. J., and Glueck, C. J., 1982, Prevalence of familial hyper-and hypolipoproteinemias-the Princeton School District Family Study, Metabolism 31:558–578.PubMedCrossRefGoogle Scholar
  13. Mendoza, S., Lutmer, R. F., Glueck, C. J., Chen, C. Y., Steiner, P. M., Fallat, R. W., and Kashyap, M. L., 1976, Composition of HDL-2 and HDL-3 in familial hyperalphalipoproteinemia, Athero sclerosis 25:131 -136.Google Scholar
  14. Morrison, J. A., Khoury, P., Laskarzewski, P., Gartside, P., Moore, M., Heiss, G., and Glueck, C. J., 1980, Hyperalphalipoproteinemia in hypercholesterolemic adults and children, Trans. Assoc. Am. Physicians 93:230–243.PubMedGoogle Scholar
  15. Namboodiri, K. K., Green, P., Kaplan, E. B., Tyroler, H. A., Morrison, J. A., Chase, G., Elston, R. C., Rifkind, B. M., and Glueck, C. J., 1983, Family aggregation of high density lipoprotein-cholesterol in random sample of white and black probands of the Lipid Research Clinics (LRC) Program. Collaborative Lipid Research Clinics Program Family Study, Arteriosclerosis 3:616–626.PubMedCrossRefGoogle Scholar
  16. Namboodiri, K. K., Green, P. P., Kaplan, E. B., Morrison, J. A., Chase, G. A., Elston, R. C., Owen,Google Scholar
  17. Rifkind, B. M., Glueck, C. J., and Tyroler, H. A., 1984, The Collaborative Lipid Research Clinics Program Family Study. IV. Familial associations of plasma lipids and lipoproteins, Am. J. Epidemiol. 119:975–996.PubMedGoogle Scholar
  18. Namboodiri, K. K., Bucher, K. D., Kaplan, E. B., Laskarzewski, P. M., Glueck, C. J., and Rifkind,Google Scholar
  19. B. M., 1985, A major gene for low levels of high density lipoprotein cholesterol: The collaborative Lipid Research Clinics Family Study, Clin. Res. 33(4):890A, 1985.Google Scholar
  20. Ordovas, J. M., Schaefer, E. J., Salem, D., Ward, R., Glueck, C. J., Vergani, C., Wilson, P. W. F., and Karathanasis, S. K., 1986, Apolipoprotein Al gene polymorphism in the 3’ flanking region associated with familial hypoalphalipoproteincemia, N. Engl. J. Med. 314:671–678.PubMedCrossRefGoogle Scholar
  21. Patsch, W., Kuisk, I., Glueck, C. J., and Schonfeld, G., 1981, Lipoproteins in familial hyperalphalipoproteinemia, Arteriosclerosis 1:156–161.PubMedCrossRefGoogle Scholar
  22. Rao, D. C., Lalouel, J. M., Suarez, B. K., Schonfeld, G., Glueck, C. J., and Siervogel, R. M., 1983, A genetic study of hyper-alpha-lipoproteinemia, Am. J. Med. Genet. 15(2): 195–203, 1983.PubMedCrossRefGoogle Scholar
  23. Third, J. H. L. C., Montag, J., Flynn, M., Friedel, J., Laskarzewski, P., and Glueck, C. J., 1984, Primary and familial hypoalphalipoproteinemia, Metabolism 33:136–146.PubMedCrossRefGoogle Scholar
  24. Tsang, R. C., Neely, K., and Glueck, C. J., 1981, Hyperalphalipoproteinemia. Birth to age 2 years, Pediatr. Res. 15:66–69.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Charles J. Glueck
    • 1
  • Ingrid Borecki
    • 1
  • D. C. Rao
    • 1
  • Peter Laskarzewski
    • 1
  1. 1.The Cholesterol CenterThe Jewish HospitalCincinnatiUSA

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