Skip to main content
SpringerLink
Log in

Gene-environment interactions in atherosclerosis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The importance of environment and genetics working together to shape an individual's risk for atherosclerosis seems intuitively obvious. However, it is only recently that research strategies have begun to evolve that attempt to answer questions related to apportionment of risk that is due to specific environmental and genetic factors. These factors may impact upon risk either singly or, more likely, through a complex interaction that affects the metabolic history of the whole organism. Because the genetic bases of lipid and lipoprotein metabolism have been well-studied, and because of the epidemiologic and pathobiochemical associations between genetic disorders of lipid metabolism and atherosclerosis, researchers have searched for gene-environment interactions within animal and human systems in which the phenotype is defined by some index of lipoprotein metabolism. From work done in the lipoprotein area to this point a clear case can be made for: 1) the genetic influence over the phenotypic response to an environmental stimulus; 2) the environmental modulation of the phenotypic expression of severe genetic defects. In the realm of gene-environment interactions that affect lipoprotein phenotype, diet is the best-studied environmental factor.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Hopkins PN, Williams RR: A survey of 246 suggested coronary risk factors. Atherosclerosis 40: 1–16, 1981

    Google Scholar 

  2. Kannel WB, Castelli WP, Gordon T, McNamara PM: Serum cholesterol, lipoproteins and the risk of coronary heart disease. The Framingham study. Ann Int Med 74: 1–9, 1971

    Google Scholar 

  3. Kannel WB, Castelli WP, Gordon T: Cholesterol in the prediction of atherosclerotic disease. New perspective based on the Framingham study. Ann Int Med 90: 85–91, 1979

    Google Scholar 

  4. Goldstein JL, Hazzard WR, Schrott HG, Bierman EL, Motulsky A: Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest 52: 1533–1543, 1973

    Google Scholar 

  5. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG: Hyperlipidemia in coronary heart disease. If. Genetic analysis of lipid levels in 176 families and definition of a new inherited disorder, combined hyperlipidemia. J Clin Invest 52: 1544–1568, 1973

    Google Scholar 

  6. Hazzard WR. Goldstein JL, Schrott HG, Motulsky AG, Bierman EL: Hyperlipidemia in coronary heart disease. III. Evaluation of lipoprotein phenotypes of 156 genetically-defined survivors of myocardial infarction. J Clin Invest 52: 1569–1577, 1973

    Google Scholar 

  7. Lewis LA, Olmstead T, Page IH, Lawry EY, Mann GV, Stare FJ, Hanig M, Lauffer MA: Serum lipid levels in normal persons. Circulation 14: 731–740, 1956

    Google Scholar 

  8. Hegele RA, Breslow JL: Apolipoprotein genetic variation in the assessment of atherosclerosis susceptibility. Genetic Epidemiology 4: 163–184, 1987

    Google Scholar 

  9. Breslow JL: Genetic basis of lipoprotein disorders. J Clin Invest 84: 373–380, 1989

    Google Scholar 

  10. Lusis AJ: Genetic factors affecting blood lipoproteins: The candidate gene approach. J Lipid Res 29: 397–429, 1988

    Google Scholar 

  11. Williams DL: Molecular biology in arteriosclerosis research. Arteriosclerosis 5: 213–227, 1985

    Google Scholar 

  12. Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK: The LDLreceptor related protein, LRP, in an apolipoprotein E-binding protein. Nature 341: 162–164, 1989

    Google Scholar 

  13. Brown MS, Herz J, Kowal R, Goldstein JL: The low density lipoprotein-receptor-related protein: Double agent or decoy? Curr Opin Lipidol 2: 65–72, 1991

    Google Scholar 

  14. Tall AR: Plasma high density lipoproteins: Metabolism and relationship to atherogenesis. J Clin Invest 86: 379–384, 1990

    Google Scholar 

  15. Scanu AM: Lipoprotein disorders: Diagnosis and treatment. In: AJ Lusis, RS Sparkes (eds.) Genetic factors in atherosclerosis: approaches and model systems. Karger, New York, 1989, pp 1–49

    Google Scholar 

  16. Brown VW, Ginsberg H: Classification and diagnosis of hyperlipidemias. In: D Steinberg, J Olefsky (eds.) Hypercholesterolemia and atherosclerosis: pathogenesis and prevention. Churchill Livingstone, New York, 1987, pp 143–168

    Google Scholar 

  17. MacCluer JW: Statistical approaches to identifying major locus susceptibility effects on disease susceptibility. In: AJ Lusis, RS Sparkes (eds.) Genetic factors in atherosclerosis: approaches and model systems. Karger, New York, 1989, pp 50–78

    Google Scholar 

  18. Elston RC, Namboordi KK, Glueck CJ, Fallat R, Tsang R, Leuba V: Study of the genetic transmission of hypercholesterolemia and hypertriglyceridemia in a 195-member kindred. Ann Hum Genet 39: 67–87, 1975

    Google Scholar 

  19. Bodurtha JN, Chen CW, Mosteller M, Nance WE, Schieken RM, Segrest J: Genetic and environmental contribution to cholesterol and its subfractions in 11-year old twins. Arterio Thromb 11: 844–850, 1991

    Google Scholar 

  20. Berg K, Kondo I, Drayna D, Lawn R: ‘Variability gene’ effect of cholesterol ester transfer protein (CETP) genes. Clin Genet 35: 437–445, 1989

    Google Scholar 

  21. Ishida BY, Paigen B: Atherosclerosis in the mouse. In: AJ Lusis, RS Sparkes (eds.) Genetic factors in atherosclerosis: approaches and model systems. Karger, New York, 1989, pp 189–222

    Google Scholar 

  22. Lusis AJ, Taylor B, Quon D, Zollman S, LeBoeuf R: Genetic factors controlling structure and expression of apolipoproteins B and E in mice. J Biol Chem 262: 5071–5078, 1983

    Google Scholar 

  23. Paigen B, Mitchell D, Reue K, Morrow A, Lusis A, LeBoeuf R: Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc Natl Acad Sci USA 84: 3763–3767, 1987

    Google Scholar 

  24. Reue K, Leete TH: Genetic variation in mouse apolipoprotein A-IV due to insertion and deletion in a region of tandem repeats. J Biol Chem 266: 12715–12721, 1991

    Google Scholar 

  25. Laber-Laird K, Rudel LL: Genetic aspects of plasma lipoproteins and cholesterol metabolism in nonhuman primate models of atherosclerosis. In: AJ Lusis, RS Sparkes (eds.) Genetic factors in atherosclerosis: approaches and model systems. Karger, New York, 1989, pp 170–188

    Google Scholar 

  26. Blangero J, MacCluer JW, Kammerer CM, Mott GE, Dyer TD, McGill Jr HC: Genetic analysis of apolipoprotein A-I in two dietary environments. Am J Human Genet 41: 414–428, 1990

    Google Scholar 

  27. Yokode M, Hammer RE, Ishibashi S, Brown MS, Goldstein JL: Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors. Science 250: 1273–1275, 1990

    Google Scholar 

  28. Rapacz J, Hasler-Rapacz J: Animal models: The pig. In: AJ Lusis, RS Sparkes (eds.) Genetic factors in atherosclerosis: approaches and model systems. Karger, New York, 1989, pp 139–169

    Google Scholar 

  29. Van Lenten BJ: Animal models: the Watanabe heritable hyperlipidemic rabbit. In: AJ Lusis, RS Sparkes (eds.) Genetic factors in atherosclerosis: approaches and model systems. Karger, New York, 1989, pp 125–138

    Google Scholar 

  30. Goldberg AC, Schoenfeld G: Effects of diet on lipoprotein metabolism. Ann Rev Nutr 5: 195–212, 1985

    Google Scholar 

  31. Mahley RW: Atherogenic hyperlipoproteinemia. The cellular and molecular biology of plasma lipoproteins altered by dietary fat and cholesterol. Med Clin North Am 66: 375–402, 1982

    Google Scholar 

  32. Blangero J, Kammerer C, Konigsberg L, Hixson J, MacCluer J: Statistical detection of genotype-environment interaction: a multivariate measured genotype approach. Am J Human Genet 45: A234, 1989.

    Google Scholar 

  33. Kagan A, Harris BR, Winkelstein Jr W, Johnson KG, Kato H, Syme L, Rhoads GG, Gay ML, Nichaman MZ, Hamilton HB, Tillotson J: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chron Dis 27: 345–364, 1970

    Google Scholar 

  34. Cox DW, Breckenridge WC, Little JA: Inheritance of apolipoprotein CII deficiency with hypertriglyceridemia and pancreatitis. N Engl J Med 299: 1421–1424, 1978

    Google Scholar 

  35. Kern F: Normal plasma cholesterol in an 88-year-old man who eats 25 eggs a day: mechanisms of adaptation. N Engl J Med 324: 899–901, 1991

    Google Scholar 

  36. Flynn MA, Nolph GB, Sun GY, Navidi M, Krause G: Effects of cholesterol and fat modification of self-selected diets on serum lipids and their specific fatty acids in normocholesterolemic and hypercholesterolemic humans. J Am Coll Nutrition 10(2): 93–106, 1991

    Google Scholar 

  37. Hegele RA, Emi M, Wu LL, Hopkins PN, Williams RR, Laloule JM: Clinical application of DNA markers in a Utah family with hypercholesterolemia. Am J Cardiol 63: 109–112, 1989

    Google Scholar 

  38. Williams RR, Hasstedt SJ, Wilson DE, Ash KO, Yanowitz FF, Reiber GE, Kuida H: evidence that men with familial hypercholesterolemia can avoid early coronary death. JAMA 255: 219–224, 1986

    Google Scholar 

  39. Weintraub MS, Eisenberg S, Breslow JL: Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E. J Clin Invest 80: 1571–1577, 1987

    Google Scholar 

  40. Mantarri M, Koskinen P, Enholm C, Huttunen JK, Manninen V: Apolipoprotein E polymorphism influences the serum cholesterol response to dietary intervention. Metabolism 40: 217–221, 1991

    Google Scholar 

  41. Tikkanen MJ, Xu C-F, Hamalainen TM, Talmud P, Sarno S, Huttunen JK, Pietinen P: XbaI polymorphism of the apolipoprotein B gene influences serum HDL cholesterol response to dietary lipid changes. Circulation 80: 379, 1989

    Google Scholar 

  42. Kaprio J, Ferrell RE, Kottke BA, Sing CF: Smoking and reverse cholesterol transport: evidence for gene-environment interaction. Clin Genet 36: 266–268, 1989

    Google Scholar 

  43. Kondo I, Berg K, Drayna D, Lawn R: DNA polymorphism at the locus for human cholesterol ester transfer protein (CETP) is associated with high density lipoprotein cholesterol and apolipoprotein levels. Clin Genet 35: 49–56, 1989

    Google Scholar 

  44. The Lipid Research Clinics Population Studies Data Book, Volume 1, The Prevalence Study, NIH Publication Number 80-1527, 1980

  45. Wilson DE, Emi M, Iverius PH, Hata A, Wu L, Hillas E, Williams RR, Lalouel JM: Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation. J Clin Invest 86: 735–750, 1990

    Google Scholar 

  46. Hegele RA, Vezina C, Moorjani S, Lupien PJ, Gagne C, Brun LD, Little JA, Connelly PW: A hepatic lipase gene mutation associated with heritable lipolytic deficiency. J Clin Endo Metab 72: 730–732, 1991

    Google Scholar 

  47. Hegele RA, Little JA, Connelly PW: Compound heterozygosity for mutant hepatic lipase in familial hepatic lipase deficiency. Biochem Biophys Res Commun 179: 73–80, 1991

    Google Scholar 

  48. Hopkins PN, Wu LL, Schumacher MC, Emi M, Hegele RA, Hunt SC, Lalouel J-M, Williams RR: Type III dyslipoproteinemia in patients heterozygous for familial hypercholesterolemia and apolipoprotein E2. Arterio Thromb 11: 1349–1355, 1991

    Google Scholar 

  49. Knopp RH, Bergelin RO, Wahl PW, Walden CE, Chapman M, Irvine S: Population-based lipoprotein lipid reference values for pregnant women compared with non-pregnant women classified by sex hormone usage. Am J Obstet Gynecol 143: 626–637, 1982

    Google Scholar 

  50. Sanderson SL, Iverius P-H, Wilson DE: Successful hyperlipemic pregnancy. JAMA 265: 1858–1860, 1991

    Google Scholar 

  51. Hegele RA, Little JA, Connelly PW: Heterozygosity for mutant lipoprotein lipase in pregnancy-induced hypertriglyceridemia. Clin Res, in press

  52. Nestruck AC, Bouthillier D, Sing CF, Davignon J: Apolipoprotein E polymorphism and plasma response to probucol. Metabolism 36: 743–747, 1987

    Google Scholar 

  53. Brown ML, Inazu A, Hesler CB, Agellon LB, Mann C, Whitlock ME, Marcel YL, Milne RW, Koizumi J, Mabuchi H, Takeda R, Tall AR: Molecular basis of lipid transfer protein deficiency in a family with increased high density lipoproteins. Nature 342: 448–451, 1989

    Google Scholar 

  54. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, Maruhama Y, Mabuchi H, Tall AR: Increased high density lipoprotein caused by a common cholesteryl ester transfer protein gene mutation. N Engl J Med 323: 1234–1238, 1990

    CAS  PubMed  Google Scholar 

  55. Leppert M, Breslow JL, Wu LL, Hasstedt S, O'Connell P, Lathrop M, Williams RR, White RL, Lalouel JM: Inference of a molecular defect of apolipoprotein B in hypobetalipoproteine mia by linkage analysis in a large kindred. J Clin Invest 82: 847–851, 1988

    Google Scholar 

  56. Hegele RA, Sutherland S, Robertson M, Wu L, Emi M, Hopkins PN, Williams RR, Lalouel J-M: The effect of genetic determinants of low density lipoprotein cholesterol levels on lipoprotein (a). Clin Invest Med 14: 146–152, 1991

    Google Scholar 

  57. Hegele RA, Connelly PW, Maguire GF, Huff MW, Leiter L, Wolfe BM, Evans AJ, Little JA: An apolipoprotein CII mutation, CIILysl9-> Thr identified in patients with hyperlipidemia. Disease Markers 9: 73–80, 1991

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Toronto, Toronto, Canada

    Robert A. Hegele

Authors
  1. Robert A. Hegele
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hegele, R.A. Gene-environment interactions in atherosclerosis. Mol Cell Biochem 113, 177–186 (1992). https://doi.org/10.1007/BF00231537

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00231537

Key words

Search

Navigation