American Heart Journal
Volume 145, Issue 6 , Pages 999-1005 , June 2003

Apolipoprotein E genotype is not associated with cardiovascular disease in heterozygous subjects with familial hypercholesterolemia

  • P Mozas, PhD

      Affiliations

    • Departamento Bioquímica, Biología Molecular-Celular, Universidad de Zaragoza, Zaragoza, Spain
  • ,
  • S Castillo

      Affiliations

    • Departamento Bioquímica, Biología Molecular-Celular, Universidad de Zaragoza, Zaragoza, Spain
  • ,
  • G Reyes

      Affiliations

    • Departamento Bioquímica, Biología Molecular-Celular, Universidad de Zaragoza, Zaragoza, Spain
  • ,
  • D Tejedor

      Affiliations

    • Departamento Bioquímica, Biología Molecular-Celular, Universidad de Zaragoza, Zaragoza, Spain
  • ,
  • F Civeira, MD, PhD

      Affiliations

    • Laboratorio Investigación Molecular, Hospital Miguel Servet, Zaragoza, Spain
  • ,
  • I García-Alvarez, MD

      Affiliations

    • Laboratorio Investigación Molecular, Hospital Miguel Servet, Zaragoza, Spain
  • ,
  • J Puzo, MD, PhD

      Affiliations

    • Laboratorio Bioquímica, Hospital San Jorge, Huesca, Spain
  • ,
  • A Cenarro, PhD

      Affiliations

    • Laboratorio Investigación Molecular, Hospital Miguel Servet, Zaragoza, Spain
  • ,
  • R Alonso, MD, PhD

      Affiliations

    • Unidad Lípidos. Fundación Jiménez Díaz, Madrid, Spain
  • ,
  • P Mata, MD, PhD

      Affiliations

    • Unidad Lípidos. Fundación Jiménez Díaz, Madrid, Spain
  • ,
  • M Pocoví, PhD

      Affiliations

    • Departamento Bioquímica, Biología Molecular-Celular, Universidad de Zaragoza, Zaragoza, Spain
    • Corresponding Author InformationReprint requests: Professor M. Pocoví, Departamento Bioquímica, Biología Molecular-Celular, Universidad de Zaragoza, Ciudad Universitaria, 50009, Zaragoza, Spain.
  • ,
  • Spanish group FH

Received 21 March 2002 ,Accepted 5 August 2002.

References 

  1. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In:  Scriver CR,  Beaudet AL,  Sly WS,  Valle D editor. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill; 1995;p. 1981–2030
  2. Heath KE, Gahan M, Whittall RA, et al.  Low-density lipoprotein receptor gene (LDLR) world-wide website in familial hypercholesterolemia (update, new features and mutation analysis). Atherosclerosis. 2001;154:243–246
  3. Scientific Steering Committee on behalf of the Simon Broome Register Group . Mortality in treated heterozygous familial hypercholesterolemia (implications for clinical management). Atherosclerosis. 1999;142:105–115
  4. Sijbrands EJ, Westendorp RG, Lombardi PM, et al.  Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia. Atherosclerosis. 2000;149:421–425
  5. Sijbrands EJ, Westendorp RG, Defesche JC, et al.  Mortality over two centuries in large pedigree with familial hypercholesterolaemia (family tree mortality study). BMJ. 2001;322:1019–1023
  6. Heiberg A, Slack J. Family similarities in the age at coronary death in familial hypercholesterolemia. BMJ. 1977;2:493–495
  7. Ferriéres J, Lambert J, Lussier-Cacan S, et al.  Coronary artery disease in heterozygous familial hypercholesterolemia patients with the same LDL receptor gene mutation. Circulation. 1995;92:290–295
  8. Wiklund O, Angelin B, Olofsson SO, et al.  Apolipoprotein(a) and ischaemic heart disease in familial hypercholesterolaemia. Lancet. 1990;335:1360–1363
  9. Seed M, Hoppichler F, Reaveley D, et al.  Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med. 1990;322:1494–1499
  10. Vuorio AF, Turtola H, Piilahti KM, et al.  Familial hypercholesterolemia in the Finnish north Karelia (a molecular, clinical, and genealogical study). Arterioscler Thromb Vasc Biol. 1997;17:3127–3138
  11. Curtiss LK, Boisvert WA. Apolipoprotein E and atherosclerosis. Curr Opin Lipidol. 2000;11:243–251
  12. Hixson JE. Apolipoprotein E polymorphism affect atherosclerosis in young males. Arterioscler Thromb. 1991;11:1237–1244
  13. Wilson PW, Schaefer EJ, Larson MG, et al.  Apolipoprotein E alleles and risk of coronary disease (a meta-analysis). Arterioscler Thromb Vasc Biol. 1996;16:1250–1255
  14. Eto M, Watanabe K, Chonan N, et al.  Familial hypercholesterolemia and apolipoprotein E4. Atherosclerosis. 1988;72:123–128
  15. De Knijff P, Stalenhoef AF, Mol MJ, et al.  Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia. Atherosclerosis. 1990;83:89–97
  16. Kitahara M, Shinomiya M, Shirai K, et al.  Frequency and role of apo E phenotype in familial hypercholesterolemia and non-familial hyperlipidemia in the Japanese. Atherosclerosis. 1990;82:197–204
  17. Hill JS, Hayden MR, Frohlich J, et al.  Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb. 1991;11:290–297
  18. Gylling H, Aalto-Setala K, Kontula K, et al.  Serum low density lipoprotein cholesterol level and cholesterol absorption efficiency are influenced by apolipoprotein B and E polymorphism and by the FH-Helsinki mutation of the low density lipoprotein receptor gene in familial hypercholesterolemia. Arterioscler Thromb. 1991;11:1368–1375
  19. Kotze MJ, De Villiers WJ, Steyn K, et al.  Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations. Arterioscler Thromb. 1993;13:1460–1468
  20. Ferriéres J, Sing CF, Roy M, et al.  Apolipoprotein E polymorphism and heterozygous familial hypercholesterolemia (sex-specific effects). Arterioscler Thromb. 1994;14:1553–1560
  21. Lindahl G, Mailly F, Humphries S, et al.  Apolipoprotein E phenotype and lipoprotein(a) in familial hypercholesterolaemia (implication for lipoprotein(a) metabolism). Clin Invest Med. 1994;72:631–638
  22. Tonstad S, Leren TP, Sivertsen M, et al.  Determinants of lipid levels among children with heterozygous familial hypercholesterolemia in Norway. Arterioscler Thromb Vasc Biol. 1995;15:1009–1014
  23. Betard C, Kessling AM, Roy M, et al.  Influence of genetic variability in the nondeletion LDL-receptor allele on phenotypic variation in French-Canadian familial hypercholesterolemia heterozygotes sharing a “null” LDL-receptor gene defect. Atherosclerosis. 1996;119:43–55
  24. Carmena-Ramon R, Real JT, Ascaso JF, et al.  Effect of apolipoprotein E genotype on lipid levels and response to diet in familial hypercholesterolemia. Nutr Metab Cardiovasc Dis. 2000;10:7–13
  25. Bertolini S, Cantafora A, Averna M, et al.  Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype. Arterioscler Thromb Vasc Biol. 2000;20:E41–E52
  26. Lambert M, Assouline L, Feoli-Fonseca JC, et al.  Determinants of lipid level variability in French-Canadian children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2001;21:979–984
  27. WHO Human Genetics Program . Familial Hypercholesterolaemia, a global perspective. Ginebra: WHO; 1999;
  28. Marcovina SM, Albers JJ, Scanu AM, et al.  Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem. 2000;46:1956–1967
  29. Miller S, Dykes D, Polensky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215
  30. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–548
  31. Pocovi M, Cenarro A, Civeira F, et al.  Incomplete dominance of type III hyperlipoproteinemia is associated with the rare apolipoprotein E2 (Arg136→Ser) variant in multigenerational pedigree studies. Atherosclerosis. 1996;122:33–46
  32. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–126
  33. van den Hoogen PC, Feskens EJ, Nagelkerke NJ, et al.  Seven Countries Study Research Group   The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world. N Engl J Med. 2000;342:1–8
  34. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, et al.  Myocardial infarction and coronary deaths in the World Health Organization MONICA Project (registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents). Circulation. 1994;90:583–612
  35. Scuteri A, Bos AJ, Zonderman AB, et al.  Is the apoE4 allele an independent predictor of coronary events?. Am J Med. 2001;110:28–32
  36. Wilson PW, Myers RH, Larson MG, et al.  The Framingham Offspring Study   Apolipoprotein E alleles, dyslipidemia, and coronary heart disease. JAMA. 1994;272:1666–1671
  37. Lahoz C, Schaefer EJ, Cupples LA, et al.  Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis. 2001;154:529–537
  38. Ilveskoski E, Perola M, Lehtimaki T, et al.  Age-dependent association of apolipoprotein E genotype with coronary and aortic atherosclerosis in middle-aged men (an autopsy study). Circulation. 1999;100:608–613
  39. Gerdes LU, Gerdes C, Kervinen K, et al.  The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction (a substudy of the Scandinavian Simvastatin Survival Study). Circulation. 2000;101:1366–1371
  40. de Knijff P, Havekes LM. Apolipoprotein E as a risk factor for coronary heart disease (a genetic and molecular biology approach). Curr Opin Lipidol. 1996;7:59–63
  41. Corbo RM, Scacchi R. Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a “thrifty” allele?. Ann Hum Genet. 1999;63(Pt 4):301–310
  42. Frikke-Schmidt R, Nordestgaard BG, Agerholm-Larsen B, et al.  Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype. J Lipid Res. 2000;41:1812–1822
  43. Davignon J, Gregg RE, Sing CF. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988;8:1–21
  44. Curtiss LK, Boisvert WA. Apolipoprotein E and atherosclerosis. Curr Opin Lipidol. 2000;11:243–251
  45. Humphries SE, Talmud PJ, Hawe E, et al.  Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke (a prospective study). Lancet. 2001;358:115–119

 Supported by grants from SAF 2001-C05, FIS 00/0952, and DGA P016/99-BM, Lácer S.A., and FUNDHICOL.P.M. and S.C. have contributed equally to this work.

PII: S0002-8703(02)94788-5

doi: 10.1016/S0002-8703(02)94788-5

American Heart Journal
Volume 145, Issue 6 , Pages 999-1005 , June 2003