Molecular Genetics of Coronary Heart Disease

  • David J. Galton
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 243)


Genes underlying the inheritance of atherosclerosis are implicated by family and twin studies. The aggregation of coronary artery disease in families has been reported by many Authors since 1948 (1). For example, Slack and Evans (,2) analysed first degree relatives of 121 men and 96 women with coronary artery disease. The increased risks of death from coronary artery disease in such relatives were five and seven-fold greater than in matched controls for males and females respectively. Familial clustering of coronary artery disease was noted especially for female patients. In Southern Finland, 104 out of 296 brothers of patients with coronary artery disease also had arterial disease compared to 8 out of 81 brothers of healthy controls (relative incidence 3.5 for brothers of probands with coronary artery disease (3) A detailed analysis of the Finish data yielded heritability estimates compatible with almost total determination of the disease by additive polygenic factors in the youngest age groups (myocardial infarction prior to the age of 46 years). In another study (4),of 207 patients who had myocardial infarcts before the age of 55 years, the highest “risk-ratios” calculated for nineteen independent variables were found with a positive family history of coronary artery disease (10.5) and lesser “risk ratios” were found with plasma cholesterol levels greater than 270 mg/dl. (4.3) cigarette smoking (4.0) and stroke in a first degree relative (3.5). The “risk ratio” for a family history of coronary artery disease was greater than that for individuals in the highest quintile of cholesterol levels. This observation may suggest that major genetic effects are not necessarily mediated by pathways of cholesterol metabolism. From this study, the heritability of coronary heart disease of early onset was calculated to be 0.63. If the families in which the proband had a monogenic hyperlipidaemia were eliminated, the heritability estimate remained as high as 0.56 (4). Equally, persuasive evidence comes from twin studies (5). Concordance rates for coronary artery disease (diagnosed by angina pectoris or myocardial infarction) in monozygotic twin pairs was found to be 0.65 compared to 0.25 in dizygotic twin pairs in a Norweigan Study.


Linkage Marker Dizygotic Twin Pair Restriction Site Polymorphism CIII Gene Uncommon Allele 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Yater WM, Traum AH, Brown WG, Fitzgerlald RP, Geisler MA, Wilcox BB. Coronary artery disease in men eighteen to thirtynine years of age. Am Heart J 36 : 334 – 372 (1948)PubMedCrossRefGoogle Scholar
  2. 2.
    Slack J, Evans KA: The increased risk of death from Ischaemic heart disease in first-degree relatives of 121 men and 96 women with ischaemic heart disease. J Med Genet 3 : 239 – 259 (1966)PubMedCrossRefGoogle Scholar
  3. 3.
    Rissanen AM. Familial aggregation of coronary heart disease in a high incidence area (North Karelia, Finland) Br Heart J. 42 : 294 – 303 (1979).PubMedCrossRefGoogle Scholar
  4. 4.
    Nora JJ, Lortscher RH, Spangler RD, Nora AH, Kimberling WJ : Genetic-epedemiologic study of early onset ischaemic heart disease. Circulation 61 : 503 – 508 (1980)PubMedGoogle Scholar
  5. 5.
    Berk K. Twin studies of coronary heart disease and its risk factors Acta Genet. Med Gemellol. 33 : 349 – 361 (1984)Google Scholar
  6. 6.
    Berg K : Genetics of coronary heart disease in Progress in Medical Genetics volume 35 ed. Steinberg AG, Beam AG, Motulsky AR, Childs B. WB Saunders, Philadelphia 1983 p 35 – 90Google Scholar
  7. 7.
    Kahler OH, Weber R : Zur erbpathologise von Herz und Kreislaufer Krankungen. Z Klin Med 137 : 507 – 575 (1940)Google Scholar
  8. 8.
    Liljefors I : Coronary heart disease in male twins. Acta Med Scand Suppl 511 (1970)Google Scholar
  9. 9.
    De Faire U : Ischaemic heart disease death in discordant twins. Acta Med Scand. Suppl 568 (1974)Google Scholar
  10. 10.
    Galton DJ : Molecular Genetics of Common Metabolic Disorders publ Ed Arnold, London (1985)Google Scholar
  11. 11.
    Bell GI, Horita S, Karam JH. A highly polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes. Diabetes 33 : 176–183 (1984)PubMedCrossRefGoogle Scholar
  12. 12.
    Hitman GA, Tarn AC, Winter RM, Williams LG, Bottazzo GF, Galton DJ. Type I (insulin-dependent) diabetes and a highly variable locus close to the insulin gene on chromosome II. Diabetologia 28 : 218–222. (1985)PubMedCrossRefGoogle Scholar
  13. 13.
    Ferns GAA, Hitman GA, Trembath R, Williams LG, Gale EA, Galton DJ. DNA polymorphic haplotypes on the short arm of chromosome II and the inheritance of Type I Diabetes Mellitus. Journal of Medical Genetics 23 : 210–216 (1986).PubMedCrossRefGoogle Scholar
  14. 14.
    Jeffrey AJ (1979). DNA sequence variants In the Gg Ag, Delta and beta globulin genes of Man : Cell 18: 1–12 (1979)CrossRefGoogle Scholar
  15. 15.
    Galton DJ: DNA polymorphisms for the Genetic Analysis of Atherosclerosis. G Schlierf, H Mori (Eds) Expanding Horizons in Atherosclerosis Research pp 187–197. Springer-Verlag Berlin 1987Google Scholar
  16. 16.
    Karathanasis SK, Zannis VI, Breslow JL: Linkage of human apolipoprotein Al and CIII genes. Nature 304 : 371–374 (1983)PubMedCrossRefGoogle Scholar
  17. 17.
    Karathanasis SK, Apolipoprotein multigene family : tandem organisation of human apolipoprotein Al, CIII and AIV genes. Proc. Natl. Acad. Sci USA 82 : 6374–6378 (1985)PubMedCrossRefGoogle Scholar
  18. 18.
    Rees A, Stocks J, Shoulders CC, Galton DJ, Baralle FE: DNA polymorphism adjacent to the human apoprotein Al gene in relation to hypertriglyceridaemia. Lancet :i 444–447 (1983)CrossRefGoogle Scholar
  19. 19.
    Seilhamer JJ, Protter AA, Frossard P, Levy-Wilson B. Isolation and DNA sequence of full length cDNA of the entire gene for human apolipoprotein Al. Discovery of a new polymorphism. DNA 3 : 309–317 (1984)PubMedCrossRefGoogle Scholar
  20. 20.
    Ferns GAA, Stocks J, Ritchie C, Galton DJ: Genetic polymorphisms of apolipoprotein CIII and insulin in survivors of myocardial infarction. Lancet i: 300–304 (1985)CrossRefGoogle Scholar
  21. 21.
    Rees A, Jowett NI, Williams LG, Stocks J, Vella MA, Camm J, Galton DJ: DNA polymorphisms flanking the insulin and apolipoprotein CIII genes and atherosclerosis. Atherosclerosis 58 : 269–275 (1985)PubMedCrossRefGoogle Scholar
  22. 22.
    Ferns GAA, Galton DJ: Haplotypes of the human apoprotein AI-CIII-AIV gene cluster in coronary atherosclerosis. Human Genetics 73 : 245–249 (1986)PubMedCrossRefGoogle Scholar
  23. 23.
    Price WH, Morris SW, Kitchin AH : Allele frequencies at five polymorphic DNA restriction enzyme sites in the apolipoprotein AI-CIII-AIV gene cluster and coronary heart disease In a Scottish Population. Clinical Sci 75 : suppl 16 pp 46P (1987)Google Scholar
  24. 24.
    Ordovas JM, Schaeffer EJ, Salem D, Ward RH, Glueck CJ, Vergani C, Wilson PWF, Karathanasis SK: Apolipoprotein Al gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinaemia. New Engl. J Med. 314 : 671–677 (1986)PubMedCrossRefGoogle Scholar
  25. 25.
    Deeb S, Failor A, Brown BG, Brunzell JD, Albers JJ, Motulsky AG: Molecular Genetics of Apolipoproteins and Coronary Heart Disease : Cold Spring Harbor Symp. Quantit. Biol. LI : 403–409 (1987)Google Scholar
  26. 26.
    Hegele RA, Herbert PN, Blum CB, Buring JE, Hennekens CH, Breslow JL : Apolipoprotein Al and All gene DMA polymorphisms and myocardial infarction (in press)Google Scholar
  27. 27.
    Frossard PM. Coleman R, Funke H, Assman G: Molecular genetics of the human apo AI-CIII-AIV gene complex. Application to Detection of Susceptibility to Atherosclerosis, ed W Hauss, R Wissler, J Grunwald. Recent Advances in Atherosclerosis Research, Westdeutscher Verlag, Dusseldorf 1987Google Scholar
  28. 28.
    Kan YW, Dozy AM: Polymorphisms of DNA sequence adjacent to human beta globin structural gene : relation to sickle cell mutation. Proc. Natl. Acad. Sci USA 75 : 5631–5636 (1978)PubMedCrossRefGoogle Scholar
  29. 29.
    Humphries SE, Williams LG, Stahenhoef AF, Baggio G, Crepaldi C, Galton DJ, Williamson R: Familial apolipoprotein CII deficiency: a preliminary analysis of the gene defect in 2 pedigrees. Human Genet. 65 : 151–156 (1984)CrossRefGoogle Scholar
  30. 30.
    Baggio G, Gabelli C, Manzato E. Martini S, Previato L, Verlato S, Brewer HB, Crepaldi C. (eds) Sirtori, Franceschini. Proceedings of NATO Advanced Research Workshop on Apolipoprotein Mutants. Apo - CII Padova: a new apoprotein variant in 2 patients with apo CII deficiency syndrome pp 203 - 210. (1986)Google Scholar
  31. 31.
    Knott TJ, Rail SC Jr. Innerarity TL, Jacobson SF, Urdea MS, Levy-Wilson B, Powell LM, Pease RJ, Eddy R, Nakai H, Byers M, Priestly LM, Robertson E, Rail LB, Betsholtz C, Shows TB, Mahley RW, Scott J. Human apolipoprotein B : Structure of carboxy-terminal domains, sites of gene expression and chromosomal localisation. Science 230 : 37–43 (1985)PubMedCrossRefGoogle Scholar
  32. 32.
    Shoulders CC, Myant N. Sidoli A, Rodriguez JC, Cortese C, Baralle FE. Molecular cloning of human LDL apolipoprotein B cDNA. Atherosclerosis 58 : 277 (1985)PubMedCrossRefGoogle Scholar
  33. 33.
    Knott TJ, Pease RJ, Powell LM, Wallis SC, Rail SC. Innerarity TL, Blackhart B, Taylor WR, Lusis AJ, McCarthy BJ, Mahley RW, Levy-Wilson B, Scott J. Human apolipoprotein B : Complete cDNA sequence and identification of domains of the protein. Nature 323 : 734–738 (1986)PubMedCrossRefGoogle Scholar
  34. 34.
    Ferns GAA, Galton DJ. Frequency of Xba I polymorphism of the apolipoprotein B Gene in Myocardial Infarct Survivors. Lancet IIi: 572 (1986)CrossRefGoogle Scholar
  35. 35.
    Hegele RA, Huang LS, Herbert PN, Blum CB, Buring JE, Hennekens CH, Breslow JL: Apolipoprotein B-gene DNA polymorphisms associated with myocardial infarction. New Engl J Med. 315 : 1509-1515CrossRefGoogle Scholar
  36. 36.
    O’Connor G, Stocks J, Lumley J, Galton DJ: A DNA polymorphism of the apolipoprotein CIII gene in extracoronary atherosclerosis Clin Sci 74 : 289–292 (1988)PubMedGoogle Scholar
  37. 37.
    Rees A, Stocks J, Sharpe CR, Shoulders CC, Jowett NI, Baralle FE, Galton DJ. DNA polymorphisms in the apo AI-CIII gene cluster : association with hypertriglyceridaemia. Journal of Clinical Investigation 76 : 1090–1095 (1985)PubMedCrossRefGoogle Scholar
  38. 38.
    Trembath RC, Thomas DJ, Hendra T, Yudkin J, Galton DJA DNA polymorphism of the apo AI-CII-AIV gene cluster associates with coronary heart disease in non-insulin dependent diabetes. Brit Med Journ. 294 : 1577–1579 (1987)CrossRefGoogle Scholar
  39. 39.
    Ferns GAA, Lanham J, Galton DJ. Polymorphisms of the apolipoprotein AI-CIII gene cluster in subjects with hypertriglyceridaemia associated with primary gout. Human Genetics 75 : 121–129 (1987)Google Scholar
  40. 40.
    Kessling AM, Horsthenke B, Humphries SE.A study of DNA polymorphisms around the human apolipoprotein Al gene In hypolipidaemic and normal subjects. Clin. Genet. : 296 - 306 (1985)Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • David J. Galton
    • 1
  1. 1.Medical Professorial Unit St. Bartholomew’s HospitalLondonUK

Personalised recommendations