Apolipoprotein E polymorphism and atherosclerosis.

The apo E locus contributes to determining the variation in plasma cholesterol levels of healthy and diseased populations. It also influences the expression of hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a complex multifactorial interaction. There is evidence that the presence of apo E2 is protective, whereas that of apo E4 predisposes to coronary artery disease. The burden of proof, however, lies on future, well-designed clinical trials and prospective studies. The study of the biological significance of the apo E polymorphism in humans has emphasized the importance of gene-gene and gene-environment interactions in the pathogenesis of hyperlipidemia and atherosclerosis. The apo E polymorphism involves the coding region of the apo E gene and results in alterations of the gene product which, in turn, either directly or secondarily affect the metabolic fate of the lipoprotein particles. Rapid advances in knowledge over the last decade have provided a metabolic explanation for the observation of the opposite effects of the epsilon 4 and the epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity which results in delayed clearance of apo E2-bearing lipoprotein particles from plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is degraded more rapidly than apo E3, and may enhance the catabolism of E4-bearing particles, leading to other alterations in lipoprotein metabolism which result in elevated levels of LDL. In view of the significant opposite impacts of the epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is evident that determination of the apo E phenotype will become a useful adjunct to the assessment of the cardiovascular risk profile of an individual. In addition, the relationship between the epsilon 2 allele and type III hyperlipoproteinemia provides a valuable model for the study of complex genetic interactions in the pathogenesis of hyperlipidemia. The further study of apo E and its interactions shows great promise for a deeper comprehension of the pathogenesis of atherosclerosis.

[1]  Y. Xie,et al.  Studies on human apolipoprotein E genetic isoforms and their phenotypes among the Chinese population. , 1987, Proceedings of the Chinese Academy of Medical Sciences and the Peking Union Medical College = Chung-kuo i hsueh k'o hsueh yuan, Chung-kuo hsieh ho i k'o ta hsueh hsueh pao.

[2]  C. Sing,et al.  Apolipoprotein E polymorphism and plasma cholesterol response to probucol. , 1987, Metabolism: clinical and experimental.

[3]  E. Boerwinkle,et al.  The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals. , 1987, American journal of medical genetics.

[4]  E. Boerwinkle,et al.  The use of measured genotype information in the analysis of quantitative phenotypes in man. , 1987, Annals of human genetics.

[5]  P. Demacker,et al.  Catabolism of chylomicron remnants in normolipidemic subjects in relation to the apoprotein E phenotype. , 1987, Journal of lipid research.

[6]  P. Wilson,et al.  Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. , 1987, Journal of lipid research.

[7]  G. Utermann,et al.  Apolipoprotein E polymorphism in health and disease. , 1987, American heart journal.

[8]  J. Ordovás,et al.  Familial apolipoprotein E deficiency. , 1986, The Journal of clinical investigation.

[9]  M. Pericak-Vance,et al.  Tight linkage of apolipoprotein C2 to myotonic dystrophy on chromosome 19 , 1986, Neurology.

[10]  R. Havel,et al.  Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in patients with familial dysbetalipoproteinemia. , 1986, The Journal of clinical investigation.

[11]  R. Gregg,et al.  Abnormal in vivo metabolism of apolipoprotein E4 in humans. , 1986, The Journal of clinical investigation.

[12]  G. Assmann,et al.  Detection of apolipoprotein E variants by an oligonucleotide "melting" procedure. , 1986, Clinical chemistry.

[13]  K. Watanabe,et al.  Reciprocal effects of apolipoprotein E alleles (ε2 AND ε4) on plasma lipid levels in normolipidemic subjects , 1986 .

[14]  T. Mohandas,et al.  Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[15]  L. Curtiss,et al.  Apolipoprotein E is a biologically active constituent of the normal immunoregulatory lipoprotein, LDL-In. , 1986, Journal of immunology.

[16]  M. Boguski,et al.  Evolution of the apolipoproteins. Structure of the rat apo-A-IV gene and its relationship to the human genes for apo-A-I, C-III, and E. , 1986, The Journal of biological chemistry.

[17]  P. Dawson,et al.  Induction of rat E and chicken A-I apolipoproteins and mRNAs during optic nerve degeneration. , 1986, The Journal of biological chemistry.

[18]  E. Boerwinkle,et al.  The use of measured genotype information in the analysis of quantitative phenotypes in man , 1986, Annals of human genetics.

[19]  H De Loof,et al.  Use of hydrophobicity profiles to predict receptor binding domains on apolipoprotein E and the low density lipoprotein apolipoprotein B-E receptor. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Ehnholm,et al.  Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. , 1986, Journal of lipid research.

[21]  R. Gregg,et al.  Abnormal low density lipoprotein metabolism in apolipoprotein E deficiency. , 1986, Journal of lipid research.

[22]  C. Luo,et al.  Structure and evolution of the apolipoprotein multigene family. , 1986, Journal of molecular biology.

[23]  J. Freeman,et al.  Nerve injury stimulates the secretion of apolipoprotein E by nonneuronal cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[24]  G. Utermann,et al.  Apolipoprotein E phenotyping from serum by Western blotting , 1986 .

[25]  V. Zannis.  Genetic polymorphism in human apolipoprotein E. , 1986, Methods in enzymology.

[26]  K. Yamakawa,et al.  Frequencies of apolipoproteins E5 and E7 in apparently healthy Japanese , 1985, The Japanese Journal of Human Genetics.

[27]  J. Breslow,et al.  Plasma and hepatic apoE isoproteins of nonhuman primates. Differences in apoE among humans, apes, and New and Old World monkeys. , 1985, Journal of lipid research.

[28]  E. Janus,et al.  Apolipoprotein E phenotypes in hyperlipidaemic patients and their implications for treatment. , 1985, Atherosclerosis.

[29]  J. Davignon,et al.  Apo E Allele Frequency in Primary Endogenous Hypertriglyceridemia (Type IV) with and without Hyperapobetalipoproteinemia , 1985, Arteriosclerosis.

[30]  H. Barakat,et al.  Characterization of plasma lipoproteins of grain- and cholesterol-fed White Carneau and Show Racer pigeons. , 1985, Journal of lipid research.

[31]  J. Taylor,et al.  Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. , 1985, The Journal of clinical investigation.

[32]  P. Forgez,et al.  A density gradient study of the lipoprotein and apolipoprotein distribution in the chicken, Gallus domesticus. , 1985, Biochimica et biophysica acta.

[33]  Y. Lin-Lee,et al.  Apolipoprotein E gene mapping and expression: localization of the structural gene to human chromosome 19 and expression of ApoE mRNA in lipoprotein- and non-lipoprotein-producing tissues. , 1985, Biochemistry.

[34]  J. Larosa,et al.  Lipoprotein and apolipoprotein levels in angiographically defined coronary atherosclerosis. , 1985, The American journal of cardiology.

[35]  G. Bruns,et al.  Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. , 1985, The Journal of biological chemistry.

[36]  I. Hjermann,et al.  Increased frequency of the apolipoprotein E‐4 isoform in male subjects with multifactorial hypercholesterolemia , 1985, Clinical genetics.

[37]  J. Taylor,et al.  Nucleotide sequence and structure of the human apolipoprotein E gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[38]  C. Sing,et al.  Role of the apolipoprotein E polymorphism in determining normal plasma lipid and lipoprotein variation. , 1985, American journal of human genetics.

[39]  P. Dawson,et al.  Quantitation of apolipoprotein E mRNA in the liver and peripheral tissues of nonhuman primates. , 1985, The Journal of biological chemistry.

[40]  E. Boerwinkle,et al.  Apolipoproteins and cardiovascular risk: Genetics and epidemiology , 1985 .

[41]  E. Boerwinkle,et al.  Strategies for elucidating the phenotypic and genetic heterogeneity of a chronic disease with a complex etiology. , 1985, Progress in clinical and biological research.

[42]  G. Utermann.  Apolipoprotein E mutants, hyperlipidemia and arteriosclerosis. , 1985, Advances in experimental medicine and biology.

[43]  J. Breslow.  Human apolipoprotein molecular biology and genetic variation. , 1985, Annual review of biochemistry.

[44]  J. Breslow,et al.  Genetic mutations affecting human lipoprotein metabolism. , 1985, Advances in human genetics.

[45]  J. Taylor,et al.  Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues of rats and marmosets. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[46]  R. Mahley,et al.  Binding of chylomicron remnants and beta-very low density lipoproteins to hepatic and extrahepatic lipoprotein receptors. A process independent of apolipoprotein B48. , 1984, The Journal of biological chemistry.

[47]  C. Packard,et al.  Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. , 1984, The Journal of clinical investigation.

[48]  R. Mahley,et al.  Plasma lipoproteins: apolipoprotein structure and function. , 1984, Journal of lipid research.

[49]  T. Sumiyoshi,et al.  New mutants of apolipoprotein E associated with atherosclerotic diseases but not to type III hyperlipoproteinemia. , 1984, The Journal of clinical investigation.

[50]  J L Witztum,et al.  Role of apolipoprotein E in the lipolytic conversion of beta-very low density lipoproteins to low density lipoproteins in type III hyperlipoproteinemia. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[51]  L. Curtiss,et al.  Cord blood plasma lipoproteins inhibit mitogen-stimulated lymphocyte proliferation. , 1984, Journal of immunology.

[52]  J. Taylor,et al.  Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant. , 1984, The Journal of biological chemistry.

[53]  Y. Matsuzawa,et al.  Increased frequency of lipoprotein disorders similar to type III hyperlipoproteinemia in survivors of myocardial infarction in Japan. , 1984, Atherosclerosis.

[54]  R. Mahley,et al.  A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1. , 1984, The Journal of clinical investigation.

[55]  A. Yamamoto,et al.  A new isoform of apolipoprotein E--apo E-5--associated with hyperlipidemia and atherosclerosis. , 1984, Atherosclerosis.

[56]  Y. Levy,et al.  [Familial dysbetalipoproteinemia]. , 1984, Harefuah.

[57]  R. Mahley,et al.  The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments. , 1983, The Journal of biological chemistry.

[58]  R. Mahley,et al.  The receptor-binding domain of human apolipoprotein E. Monoclonal antibody inhibition of binding. , 1983, The Journal of biological chemistry.

[59]  J. Segrest,et al.  Resistance of a very low density lipoprotein subpopulation from familial dysbetalipoproteinemia to in vitro lipolytic conversion to the low density lipoprotein density fraction. , 1983, Journal of lipid research.

[60]  C. Sing,et al.  Apolipoprotein E phenotyping with a single gel method: application to the study of informative matings. , 1983, Journal of lipid research.

[61]  D. Steinberg.  Lipoproteins and atherosclerosis. A look back and a look ahead. , 1983, Arteriosclerosis.

[62]  G. Assmann,et al.  Apolipoprotein E Polymorphism and Coronary Artery Disease , 1983, Arteriosclerosis.

[63]  R. Havel,et al.  Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. , 1983, The Journal of clinical investigation.

[64]  R. Mahley,et al.  Lipoprotein receptors and cholesterol homeostasis. , 1983, Biochimica et biophysica acta.

[65]  C. Blum,et al.  Apolipoprotein E synthesis in human kidney, adrenal gland, and liver. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[66]  E. Janus,et al.  Genetic variation in human apolipoprotein E. , 1982, Journal of lipid research.

[67]  J. Little,et al.  Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. , 1982, Atherosclerosis.

[68]  M. Brown,et al.  Biochemical and genetic studies of the apoprotein E secreted by mouse macrophages and human monocytes. , 1982, The Journal of biological chemistry.

[69]  R. Gregg,et al.  PHENOTYPE STUDY OF APOLIPOPROTEIN E ISOFORMS IN HYPERLIPOPROTEINAEMIC PATIENTS , 1982, The Lancet.

[70]  R. Mahley,et al.  Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[71]  R. Gregg,et al.  Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia. , 1982, The Journal of clinical investigation.

[72]  R J Havel,et al.  Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. , 1982, Journal of lipid research.

[73]  R. Mahley,et al.  Human apolipoprotein E. The complete amino acid sequence. , 1982, The Journal of biological chemistry.

[74]  R. Mahley,et al.  Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. , 1982, The Journal of biological chemistry.

[75]  G. Utermann.  Apolipoprotein E (role in lipoprotein metabolism and pathophysiology of hyperlipoproteinemia type III). , 1982, La Ricerca in clinica e in laboratorio.

[76]  R. Mahley,et al.  Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. , 1981, The Journal of clinical investigation.

[77]  R. Mahley,et al.  Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. , 1981, The Journal of biological chemistry.

[78]  R. Ross.  George Lyman Duff Memorial Lecture. Atherosclerosis: a problem of the biology of arterial wall cells and their interactions with blood components. , 1981, Arteriosclerosis.

[79]  R. Levy.  Declining mortality in coronary heart disease. , 1981, Arteriosclerosis.

[80]  J. Breslow,et al.  Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. , 1981, Biochemistry.

[81]  R. Gregg,et al.  Type III hyperlipoproteinemia: defective metabolism of an abnormal apolipoprotein E. , 1981, Science.

[82]  R. Mahley,et al.  Immunoregulatory plasma lipoproteins. Role of apoprotein E and apoprotein B. , 1980, The Journal of biological chemistry.

[83]  Y. Chao,et al.  Isoprotein specificity in the hepatic uptake of apolipoprotein E and the pathogenesis of familial dysbetalipoproteinemia. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[84]  R. Mahley,et al.  Rapid hepatic clearance of the canine lipoproteins containing only the E apoprotein by a high affinity receptor. Identity with the chylomicron remnant transport process. , 1980, The Journal of biological chemistry.

[85]  J. Breslow,et al.  Characterization of a unique human apolipoprotein E variant associated with type III hyperlipoproteinemia. , 1980, The Journal of biological chemistry.

[86]  W. Meyers,et al.  Effect of apoproteins on hepatic uptake of triglyceride emulsions in the rat. , 1980, The Journal of clinical investigation.

[87]  G. Vega,et al.  Apolipoproteins in human cerebrospinal fluid. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[88]  B. Suarez,et al.  Type III hyperlipoproteinemia: development of a VLDL ApoE gel isoelectric focusing technique and application in family studies. , 1979, The Journal of laboratory and clinical medicine.

[89]  G. Utermann,et al.  Polymorphism of apolipoprotein E , 1979, Clinical genetics.

[90]  P. Bachorik,et al.  Effects of genetic mechanisms on plasma lipoprotein metabolism and the pathogenesis of atherosclerosis. , 1979, Progress in clinical and biological research.

[91]  R. Mahley,et al.  Apoprotein (E--A-II) complex of human plasma lipoproteins. I. Characterization of this mixed disulfide and its identification in a high density lipoprotein subfraction. , 1978, The Journal of biological chemistry.

[92]  G. Utermann,et al.  Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man , 1977, Nature.

[93]  C. Sing,et al.  Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. III. Identification of genetic effects using 12 polymorphic genetic blood marker systems. , 1976, American journal of human genetics.

[94]  M. Halperin,et al.  Estimation of the multivariate logistic risk function: a comparison of the discriminant function and maximum likelihood approaches. , 1971, Journal of chronic diseases.

[95]  R. Mahley,et al.  Identification of a New Structural Variant of Human Apolipoprotein E , E 2 ( Lys , 46 , Gln ) , in a Type III Hyperlipoproteinemic Subject with the E 3 / 2 Phenotype , 2022 .