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Apolipoprotein genes and atherosclerosis

  • Heinrich Wieland — Prize Lecture
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Summary

In order to elucidate the genetic abnormalities underlying lipoprotein disorders associated with coronary heart disease susceptibility, researchers have looked for candidate genes. The studies have focused particularly on the lipoprotein transport genes. Relatively common as well as rare mutations have already been identified in several of these genes. In addition, further metabolic and genetic studies indicate that some of these loci harbor significant, but as yet undefined, genetic variation. In the next few years, it is not unreasonable to expect that all or most of the significant mutations at these loci will be catalogued. It is too early to know whether this will be sufficient to explain the genetic basis of altered lipoprotein levels or whether new loci will need to be investigated. Additional candidate gene loci might be those coding for genes involved in intracellular cholesterol metabolism, cholesterol absorption, or insulin resistance. New loci may also be revealed by the technique of reverse genetics. A more complete understanding of the genetics of atherosclerosis susceptibility will probably also entail the identification of variants at genetic loci that control both the reaction of the blood vessel wall to atherogenic lipoproteins and the thrombosis system. Investigation of the genetic basis of coronary heart disease susceptibility remains a worthwhile and lively field, with important clinical and public health ramifications.

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Abbreviations

LPL:

lipoprotein lipase

HL:

hepatic lipase

LCAT:

ecithin cholesteryl acyltransferase

CETP:

cholesteryl ester transfer protein

RFLP:

restriction fragment length polymorphism

FCR:

fractional catabolic rate

HDL, LDL, VLDL, SDL:

high, low, very low, intermediate density lipoproteins

References

  1. Aalto-Setala K, Helve E, Kovanen RT, Kontula K (1989) Finnish type of low density lipoprotein receptor gene mutation (FH-Helsinki) deletes exons encoding the carboxy-terminal part of the receptor and creates an internalization-defective phenotype. J Clin Invest 84:499–505

    Google Scholar 

  2. Berg K (1963) A new serum type system in man: the Lp system. Acta Pathol Microbiol Scand 59:369–382

    Google Scholar 

  3. Blackhart BD, Ludwig EM, Pierotti VR, Caiati L, Onasch MA, et al (1986) Structure of the human apolipoprotein B gene. J Biol Chem 261:15364–15367

    Google Scholar 

  4. Breslow JL (1989) Familial disorders of high density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1251–1266

    Google Scholar 

  5. Breslow JL (1991) Lipoprotein transport gene abnomalities underlying coronary heart disease susceptibility. Annu Rev Med 42:357–371

    Google Scholar 

  6. Brinton EA, Eisenberg S, Breslow JL (1989) Elevated high density lipoprotein cholesterol levels correlate with decreased apo A-I and apo A-II fractional catabolic rate in women. J Clin Invest 84:262–269

    Google Scholar 

  7. Brinton EA, Eisenberg S, Breslow JL (1990) A low fat diet decreases HDL-cholesterol levels by decreasing HDL apolipoprotein rates. J Clin Invest 85:144–151

    Google Scholar 

  8. Brinton EA, Eisenberg S, Breslow JL (1991) Increased apo A-I and apo A-II fractional catabolic rate in patients with low HDL-cholesterol levels with or without hypertriglyceridemia. J Clin Invest 87:536–544

    Google Scholar 

  9. Brown ML, Inazu A, Hesler CB, Agellon LB, Mann C, et al (1989) Molecular basis of lipid transfer protein deficiency in a family with increased high-density lipoproteins. Nature 342:448–451

    Google Scholar 

  10. Chen S-H, Habib E, Yang C-Y, Gu Z-W,, Lee BR, et al (1987) Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science 238:363–366

    Google Scholar 

  11. Connelly PW, Maguire GF, Lee M, Little JA (1990) Plasma lipoproteins in familial hepatic lipase deficiency. Arteriosclerosis 10:40–48

    Google Scholar 

  12. Cortner JA, Coates PM, Le NA, Cryer DD, Ragni MC, et al (1987) Kinetics of chylomicron remnant clearance in normal and hyperlipoproteinemic subjects. J Lipid Res 28:195–206

    Google Scholar 

  13. Dahlen GH, Guyton JR, Attar M, Farmer JA, Kautz JA, et al (1986) Association of levels of lipoprotein Lp(a), plasma lipids, and other proteins with coronary artery disease documented by angiography. Circulation 74:758–765

    Google Scholar 

  14. Das HK, McPherson J, Bruns GAP, Karathanasis SK, Breslow JL (1985) Isolation, characterization and mapping to chromosome 19 of the human apolipoprotein E gene. J Biol Chem 260:6240–6247

    Google Scholar 

  15. Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and athersoclerosis. Arteriosclerosis 8:1–21

    CAS  PubMed  Google Scholar 

  16. Demant T, Carlson LA, Holmquist L, Karpe F, Nilsson-Ehle P, et al (1988) Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein. J Lipid Res 29:1603–1611

    Google Scholar 

  17. Eckardstein A von, Funke H, Henke A, Altland K, Benninghoven A, et al (1989) Apolipoprotein A-I variants: naturally occurring substitutions of proline residues affect plasma concentration of apolipoprotein A-I. J Clin Invest 84:1722–1730

    Google Scholar 

  18. Eckardstein A von, Funke H, Walter M, Altland K, Benninghoven A, et al (1990) Structural analysis of human apolipoprotein A-I variants. J Biol Chem 265:8610–8617

    Google Scholar 

  19. Eisenberg S (1984) High density lipoprotein metabolism. J Lipid Res 25:1017–1058

    Google Scholar 

  20. Farese RV Jr, Linton MF, Young SG (1991) Apolipoprotein B gene mutations affecting cholesterol levels. J Int Med (in press)

  21. Fojo S, Brewer HB Jr (1992) Hypertriglyceridemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. J Int Med (in press)

  22. Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW (1980) AIMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest 66:892–900

    Google Scholar 

  23. Gaubatz JW, Heideman C, Gotto AM Jr, Morrisett JD, Dahlen GH (1982) Human plasma lipoprotein(a): structural properties. J Biol Chem 258:4582–4589

    Google Scholar 

  24. Gavish D, Azrolan N, Breslow JL (1989) Plasma Lp(a) concentration is inversely correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene. J Clin Invest 84:2021–2027

    Google Scholar 

  25. Goldstein JL, Brown MS (1989) Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly VS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGrawHill, New York, pp 1215–1250

    Google Scholar 

  26. Havel JH, Kane JP (1989) Lipoprotein and lipid metabolism disorders. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw Hill, New York, pp 1129–1138

    Google Scholar 

  27. Hobbs HH, Brown MS, Russell DW, Davignon J, Goldstein JL (1987) Deletion in the gene for the low-density-lipoprotein-receptor in a majority of French Canadians with familial hypercholesterolemia. N Engl J Med 317:734–737

    Google Scholar 

  28. Huang L-S, Miller DA, Bruns GAP, Breslow JL (1986) Mapping of the human apo B gene to chromosome 2p and demonstration of a two allele RFLP. Proc Natl Acad Sci USA 83:644–648

    Google Scholar 

  29. Huang L-S, Ripps ME, Korman SH, Deckelbaum RJ, Breslow JL (1989) Hypobetalipoproteinemia due to an apolipoprotein B gene exon 21 deletion derived by Alu-Alu recombination. J Biol Chem 264:11394–11400

    Google Scholar 

  30. Innerarity TL, Weisgraber KH, Arnold KS, Mahley RW, Krauss RM, et al (1987) Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 84:6919–6923

    Google Scholar 

  31. Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL (1990) Hypertriglyceridemia as a result of human apolipoprotein CIII gene expression in transgenic mice. Science 249:790–793

    Google Scholar 

  32. Karathanasis SK (1985) Apolipoprotein multigene family: tandem organization of human apolipoprotein AI, CIII, and AIV genes. Proc Natl Acad Sci USA 82:6374–6378

    Google Scholar 

  33. Karathanasis SK, Zannis VI, Breslow JL (1983) Isolation and characterization of the human apolipoprotein A-I gene. Proc Natl Acad Sci USA 80:6147–6151

    Google Scholar 

  34. Karathanasis SK, McPherson J, Zannis VI, Breslow JL (1983) Linkage of human apolipoprotein A-I and C-III genes. Nature 304:371–373

    Google Scholar 

  35. Karathanasis SK, Norum RA, Zannis VI, Breslow JL (1983) An inherited polymorphism in the human apolipoprotein A-I gene locus related to the development of atherosclerosis. Nature 301:718–720

    CAS  PubMed  Google Scholar 

  36. Karathanasis SK, Zannis VI, Breslow JL (1983) A DNA insertion in the apolipoprotein A-I gene locus related to the development of atherosclerosis. Nature 305:823–825

    Google Scholar 

  37. Karathanasis SK, Ferris E, Haddad IA (1987) DNA inversion within the apolipoprotein AI/CIII/AIV-encoding gene clusters of certain patients with premature atherosclerosis. Proc Natl Acad Sci USA 84:7198–7202

    Google Scholar 

  38. Koizummi JH, Mabuchi A, Yoshimura I, Michishita M, Takeda H, et al (1985) Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinemia. Atherosclerosis 58:175–186

    Google Scholar 

  39. Kurasawa T, Yokoyama S, Miyake Y, Yamamura Y, Yamamato A (1985) Rate of cholesteryl ester transfer between high and low density lipoproteins in human serum and a case with decreased transfer rate in association with hyperalphalipoproteinemia. J Biochem 98:1499–1508

    Google Scholar 

  40. Lackner C, Boerwinkle E, Leffert CC, Rahmig T, Hobbs HH (1991) Molecular basis of apolipoprotein(a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis. J Clin Invest 87:2153–2161

    Google Scholar 

  41. Lehrman MA, Schneider WJ, Brown MS, Davis CG, Elhammer A, et al (1987) The Lebanese allele at the LDL receptor locus: nonsense mutation produces truncated receptor that is retained in endoplasmic reticulum. J Biol Chem 262:401–410

    Google Scholar 

  42. Leitersdorf E, Westhuyzen DR Van Der, Coetzee GA, Hobbs HH (1989) Two common low density lipoprotein receptor gene mutations cause familial hypercholesterolemia in Afrikaners. J Clin Invest 84:954–961

    Google Scholar 

  43. Leitersdorf E, Tobin EJ, Davignon J, Hobbs HH (1990) Common low-density lipoprotein receptor mutations in the French Canadian population. J Clin Invest 85:1014–1023

    Google Scholar 

  44. Leppert M, Breslow JL, Wu L, Hasstedt S, O'Connell P, et al (1988) Inference of a molecular defect of apolipoprotein B in hypobetalipoproteinemia by linkage analysis in a large kindred. J Clin Invest 82:847–851

    Google Scholar 

  45. The Lipid Research Clinics Population Studies Data Book (1980) The prevalence study, vol 1. (NIH publ. 80–1527) US Dept Health and Human Services, Natl Inst Health, Bethesda

    Google Scholar 

  46. Mahley RW, Rall SC Jr (1989) Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1195–1213

    Google Scholar 

  47. Matsunaga T, Hiasa Y, Yanagi H, Maeda T, Hattori N, Yamakawa K, Yamanouchi Y, Tanaka I, Obara T, Hamaguchi H (1991) Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. Proc Natl Acad Sci USA 88:2793–2797

    CAS  PubMed  Google Scholar 

  48. McLean JW, Tomlinson JE, Kuang W-J, Eaton DL, Chen EY, et al (1987) cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 330:132–137

    Google Scholar 

  49. Nichols WC, Dwulet FE, Liepnicks J, Benson MD (1988) Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun 156:762–768

    Google Scholar 

  50. Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, et al (1982) Familial deficiency of apolipoproteins A-I and C-III and precocious coronary artery disease. N Engl J Med 306:1513–1519

    Google Scholar 

  51. Norum KR, Gjone E, Glomset JA (1989) Familial lecithin: cholesterol acyltransferase deficiency including fish eye disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1181–1194

    Google Scholar 

  52. Ordovas JM, Cassidy DK, Civeira F, Bisgaier CL, Schaefer EJ (1989) J Biol Chem 264:16339–16342

    Google Scholar 

  53. Paik YK, Chang DJ, Reardon CA, Davies GE, Mahley RW, et al (1985) Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci USA 82:3445–3449

    Google Scholar 

  54. Powell LM, Wallis SC, Pense RJ, Edwards YH, Knott TJ, et al (1987) A novel form of tissue-specific RNA processing produces apolipoprotein B-48 in intestine. Cell 50:831–840

    Google Scholar 

  55. Rall SC, Weisgraber KH, Mahley RW (1981) Human apolipoprotein E. J Biol Chem 257:4171–4178

    Google Scholar 

  56. Rhoads GG, Dahlen G, Berg K, Morton NE, Dannenberg AL (1986) Lp(a) lipoprotein as a risk factor for myocardial infarction. J Am Med Assoc 256:2540–2544

    Google Scholar 

  57. Scanu A (1990) Lipoprotein(a): heterogeneity and biological relevance. J Clin Invest 85:1709–1715

    Google Scholar 

  58. Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB Jr (1982) Plasma apolipoprotein A-I absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease. Arteriosclerosis 2:16–26

    Google Scholar 

  59. Schmitz G, Lackner K (1989) In: Crepaldi G, Gotto AM, Manzato E, Baggio G (eds) Atherosclerosis, vol 8. Excerpta Medica, Amsterdam, pp 399–403

    Google Scholar 

  60. Schmitz G, Assmann G, Robenek H, Brennhausen B (1985) Tangier disease: a disorder of intracellular membrane traffic. Proc Natl Acad Sci USA 82:6305–6309

    Google Scholar 

  61. Schneider WJ, Kovanen PT, Brown MS, Goldstein JL, Utermann G, et al (1981) Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenals of rats, rabbits, and cows. J Clin Invest 68:1075–1085

    Google Scholar 

  62. Shaefer EJ, Blum CB, Levy RI, Jenkins LL, Alaupovic P, et al (1978) Metabolism of high density lipoprotein apolipoproteins in Tangier disease. N Engl J Med 299:905–910

    Google Scholar 

  63. Shoulders CC, Kornblihtt AR, Munro BS, Baralle FE (1983) Gene structure of human apolipoprotein AI. Nucleic Acids Res 11:2827–2837

    Google Scholar 

  64. Soria LF, Ludwig EH, Clarke HRG, Vega GL, Grundy SM, et al (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 86:587–591

    Google Scholar 

  65. Sudhof TC, Goldstein JL, Brown MS, Russell DW (1985) The LDL receptor gene: a mosaic of exons shared with different proteins. Science 228:815–822

    Google Scholar 

  66. Utermann G (1989) The mysteries of lipoprotein(a). Science 246:904–910

    Google Scholar 

  67. Utermann G, Weber W (1983) Protein composition of Lp(a), lipoprotein from human plasma. FEBS Lett 154:357–361

    Google Scholar 

  68. Utermann G, Menzel HJ, Kraft HG, Duba HC, Kemmler HG, et al (1987) Lp(a) glycoprotein phenotypes: inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. J Clin Invest 80:458–465

    Google Scholar 

  69. Vega GL, Grundy SM (1986) In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia. J Clin Invest 78:1410–1414

    Google Scholar 

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

    Google Scholar 

  71. Weintraub MS, Eisenberg S, Breslow JL (1987) Different patterns of postprandial metabolism in normals, and type IIa, type III and type IV hyperlipoproteinemics. Effects of treatment with cholestyramine and gemfibrozil. J Clin Invest 79:1110–119

    Google Scholar 

  72. Weisgraber KH, Rall SC Jr, Bersot TP, Mahley RW (1983) Apolipoprotein AIMilano. Detection of normal A-I in affected subjects and evidence for a cysteine for arginine substitution in the variant A-I. J Biol Chem 258:2508–2513

    Google Scholar 

  73. Zannis VI, Breslow JL (1981) Human VLDL apo E isoprotein polymorphism is explained by genetic variation and post-translational modification. Biochemistry 20:1033–1041

    Google Scholar 

  74. Zannis VI, Just PW, Breslow JL (1981) Human apolipoprotein E isoprotein subclasses are genetically determined. Am J Hum Genet 33:11–24

    Google Scholar 

  75. Zannis VI, Breslow JL, Utermann G, Mahley R, Weisgraber KH, et al (1982) Proposed nomenclature of apo E isoprotein genotypes and phenotypes. J Lipid Res 23:911–914

    Google Scholar 

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  1. Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York

    J. L. Breslow

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Breslow, J.L. Apolipoprotein genes and atherosclerosis. Clin Investig 70, 377–384 (1992). https://doi.org/10.1007/BF00235516

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