American Journal of Cardiology
Volume 104, Issue 10, Supplement , Pages 22E-31E , 16 November 2009

The Genetics of High-Density Lipoprotein Metabolism: Clinical Relevance for Therapeutic Approaches

References 

  1. Lewis SJ. Prevention and treatment of atherosclerosis: a practitioner's guide for 2008. Am J Med. 2009;122:S38–S50
  2. Gotto AM, Brinton EA. Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. J Am Coll Cardiol. 2004;43:717–724
  3. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497
  4. Gordon DJ, Rifkind BM. High-density lipoprotein—the clinical implications of recent studies. N Engl J Med. 1989;321:1311–1316
  5. Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid—a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin. 2004;20:1253–1268
  6. Holleboom AG, Vergeer M, Hovingh GK, Kastelein JJ, Kuivenhoven JA. The value of HDL genetics. Curr Opin Lipidol. 2008;19:385–394
  7. Huuskonen J, Olkkonen VM, Jauhiainen M, Ehnholm C. The impact of phospholipid transfer protein (PLTP) on HDL metabolism. Atherosclerosis. 2001;155:269–281
  8. Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev. 2006;58:342–374
  9. Hovingh GK, de Groot E, van der Steeg W, Boekholdt SM, Hutten BA, Kuivenhoven JA, et al. Inherited disorders of HDL metabolism and atherosclerosis. Curr Opin Lipidol. 2005;16:139–145
  10. Klos KL, Kullo IJ. Genetic determinants of HDL: monogenic disorders and contributions to variation. Curr Opin Cardiol. 2007;22:344–351
  11. Favari E, Gomaraschi M, Zanotti I, Bernini F, Lee-Rueckert M, Kovanen PT, et al. A unique protease-sensitive high density lipoprotein particle containing the apolipoprotein A-I(Milano) dimer effectively promotes ATP-binding cassette A1-mediated cell cholesterol efflux. J Biol Chem. 2007;282:5125–5132
  12. Bielicki JK, Oda MN. Apolipoprotein A-I(Milano) and apolipoprotein A-I(Paris) exhibit an antioxidant activity distinct from that of wild-type apolipoprotein A-I. Biochemistry. 2002;41:2089–2096
  13. Gualandri V, Franceschini G, Sirtori CR, Gianfranceschi G, Orsini GB, Cerrone A, et al. AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission. Am J Hum Genet. 1985;37:1083–1097
  14. Sirtori CR, Calabresi L, Franceschini G, Baldassarre D, Amato M, Johansson J, et al. Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation. 2001;103:1949–1954
  15. Hovingh GK, Brownlie A, Bisoendial RJ, Dube MP, Levels JH, Petersen W, et al A novel apoA-I mutation (L178P) leads to endothelial dysfunction, increased arterial wall thickness, and premature coronary artery disease. J Am Coll Cardiol. 2004;44:1429–1435
  16. Miller M, Aiello D, Pritchard H, Friel G, Zeller K. Apolipoprotein A-I(Zavalla) (Leu159–>Pro): HDL cholesterol deficiency in a kindred associated with premature coronary artery disease. Arterioscler Thromb Vasc Biol. 1998;18:1242–1247
  17. Moriyama K, Sasaki J, Takada Y, Matsunaga A, Fukui J, Albers JJ, et al. A cysteine-containing truncated apo A-I variant associated with HDL deficiency. Arterioscler Thromb Vasc Biol. 1996;16:1416–1423
  18. Recalde D, Velez-Carrasco W, Civeira F, Cenarro A, Gomez-Coronado D, Ordovas JM, et al. Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apo A-I(Zaragoza) (L144R). Atherosclerosis. 2001;154:613–623
  19. Krimbou L, Jahagirdar R, Bailey D, Hafiane A, Ruel I, Wong N, et al. Compound RVX-208 modulates HDL-C levels and function in non-human primates and in early (phase I) human trials. Circulation. 2008;118:S_371;Abstract 1696
  20. Chiesa G, Parolini C, Sirtori CR. Acute effects of high-density lipoproteins: biochemical basis and clinical findings. Curr Opin Cardiol. 2008;23:379–385
  21. Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I: potential reverse cholesterol transport in humans. Circulation. 1999;100:594–598
  22. Nanjee MN, Cooke CJ, Garvin R, Semeria F, Lewis G, Olszewski WL, et al. Intravenous apoA-I/lecithin discs increase pre-β-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res. 2001;42:1586–1593
  23. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292–2300
  24. Tardif JC, Gregoire J, L'Allier PL, Ibrahim R, Lesperance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297:1675–1682
  25. Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G, et al. Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 2002;105:290–292
  26. Van Lenten BJ, Wagner AC, Anantharamaiah GM, Navab M, Reddy ST, Buga GM, et al. Apolipoprotein A-I mimetic peptides. Curr Atheroscler Rep. 2009;11:52–57
  27. Bloedon LT, Dunbar R, Duffy D, Pinell-Salles P, Norris R, DeGroot BJ, et al. Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients. J Lipid Res. 2008;49:1344–1352
  28. Jahagirdar R, Genest J, Hansen HC, Nicholls CD, Attwell S, McLure KG, et al. RVX-208: A small molecule that increases ApoA-I, HDL-C, and cholesterol efflux. Atheroscler Suppl. 2008;9:2
  29. Burgess JW, Neville TA, Rouillard P, Harder Z, Beanlands DS, Sparks DL. Phosphatidylinositol increases HDL-C levels in humans. J Lipid Res. 2005;46:350–355
  30. Glomset JA. The plasma lecithins: cholesterol acyltransferase reaction. J Lipid Res. 1968;9:155–167
  31. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, et al Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999;22:336–345
  32. Brunham LR, Singaraja RR, Hayden MR. Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. Annu Rev Nutr. 2006;26:105–129
  33. Hersberger M, von EA. Modulation of high-density lipoprotein cholesterol metabolism and reverse cholesterol transport. Handb Exp Pharmacol. 2005;537–561
  34. Haghpassand M, Bourassa PA, Francone OL, Aiello RJ. Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Invest. 2001;108:1315–1320
  35. van Dam MJ, de Groot E, Clee SM, Hovingh GK, Roelants R, Brooks-Wilson A, et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet. 2002;359:37–42
  36. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 2000;289:1524–1529
  37. Lu TT, Repa JJ, Mangelsdorf DJ. Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism. J Biol Chem. 2001;276:37735–37738
  38. Miao B, Zondlo S, Gibbs S, Cromley D, Hosagrahara VP, Kirchgessner TG, et al. Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator. J Lipid Res. 2004;45:1410–1417
  39. Rader DJ. Liver X receptor and farnesoid X receptor as therapeutic targets. Am J Cardiol. 2007;100(suppl):n15–n19
  40. Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:160–167
  41. Shah PK. Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease. Eur Heart J. 2007;28:5–12
  42. Koizumi J, Mabuchi H, Yoshimura A, Michishita I, Takeda M, Itoh H, et al. Deficiency of serum cholesteryl-ester transfer activity in patients with familial hyperalphalipoproteinaemia. Atherosclerosis. 1985;58:175–186
  43. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323:1234–1238
  44. Inazu A, Jiang XC, Haraki T, Yagi K, Kamon N, Koizumi J, et al Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol. J Clin Invest. 1994;94:1872–1882
  45. Sviridov D, Nestel PJ. Genetic factors affecting HDL levels, structure, metabolism and function. Curr Opin Lipidol. 2007;18:157–163
  46. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996;97:2917–2923
  47. Curb JD, Abbott RD, Rodriguez BL, Masaki KH, Curb JD, Petrovitch H. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res. 2004;45:948–953
  48. Moriyama Y, Okamura T, Inazu A, Doi M, Iso H, Mouri Y, et al. A low prevalence of coronary heart disease among subjects with increased high-density lipoprotein cholesterol levels, including those with plasma cholesteryl ester transfer protein deficiency. Prev Med. 1998;27:659–667
  49. Boekholdt SM, Sacks FM, Jukema JW, Shepherd J, Freeman DJ, McMahon AD, et al Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects. Circulation. 2005;111:278–287
  50. van Acker BA, Botma GJ, Zwinderman AH, Kuivenhoven JA, Dallinga-Thie GM, Sijbrands EJ, et al. High HDL cholesterol does not protect against coronary artery disease when associated with combined cholesteryl ester transfer protein and hepatic lipase gene variants. Atherosclerosis. 2008;200:161–167
  51. Bruce C, Sharp DS, Tall AR. Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia. J Lipid Res. 1998;39:1071–1078
  52. Thompson A, Di Angelantonio E, Sarwar N, Erqou S, Saleheen D, Dullaart RP, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA. 2008;299:2777–2788
  53. Davidson MH, McKenney JM, Shear CL, Revkin JH. Efficacy and safety of torcetrapib, a novel cholesteryl ester transfer protein inhibitor, in individuals with below-average high-density lipoprotein cholesterol levels. J Am Coll Cardiol. 2006;48:1774–1781
  54. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, et al Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122
  55. Hu X, Dietz JD, Xia C, Knight DR, Loging WT, Smith AH, et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150:2211–2219
  56. Forrest MJ, Bloomfield D, Briscoe RJ, Brown PN, Cumiskey AM, Ehrhart J, et al Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154:1465–1473
  57. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002;105:2159–2165
  58. Stroes ES, Kastelein JJ, Bernardeau A, Blum D, Clerc RG, Campos L, et al. Absence of effect of R1658/JTT-705 on blood pressure and tissue expression of renin-angiotensin system related genes in rats [abstract]. J Am Coll Cardiol. 2008;51(suppl 1):A322
  59. Bloomfield D, Carlson GL, Sapre A, Tribble D, McKenney JM, Littlejohn TW, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157:352–360
  60. Jaye M, Lynch KJ, Krawiec J, Marchadier D, Maugeais C, Doan K, et al. A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet. 1999;21:424–428
  61. Paradis ME, Badellino KO, Rader DJ, Deshaies Y, Couture P, Archer WR, et al. Endothelial lipase is associated with inflammation in humans. J Lipid Res. 2006;47:2808–2813
  62. Ishida T, Choi S, Kundu RK, Hirata K, Rubin EM, Cooper AD, et al. Endothelial lipase is a major determinant of HDL level. J Clin Invest. 2003;111:347–355
  63. Jensen MK, Rimm EB, Mukamal KJ, Edmondson AC, Rader DJ, Vogel U, et al. The T111I variant in the endothelial lipase gene and risk of coronary heart disease in three independent populations. Eur Heart J. 2009;30:1584–1589
  64. Edmondson AC, Brown RJ, Kathiresan S, Cupples LA, Demissie S, Manning AK, et al Loss-of-function variants in endothelial lipase are a cause of elevated HDL cholesterol in humans. J Clin Invest. 2009;119:1042–1050
  65. Rye KA, Hime NJ, Barter PJ. Evidence that cholesteryl ester transfer protein-mediated reductions in reconstituted high density lipoprotein size involve particle fusion. J Biol Chem. 1997;272:3953–3960
  66. Schgoer W, Mueller T, Jauhiainen M, Wehinger A, Gander R, Tancevski I, et al Low phospholipid transfer protein (PLTP) is a risk factor for peripheral atherosclerosis. Atherosclerosis. 2008;196:219–226
  67. Schlitt A, Bickel C, Thumma P, Blankenberg S, Rupprecht HJ, Meyer J, et al. High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol. 2003;23:1857–1862
  68. Schlitt A, Blankenberg S, Bickel C, Lackner KJ, Heine GH, Buerke M, et al. PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study. J Lipid Res. 2009;50:723–729
  69. de Vries R, Dallinga-Thie GM, Smit AJ, Wolffenbuttel BH, van Tol A, Dullaart RP. Elevated plasma phospholipid transfer protein activity is a determinant of carotid intima-media thickness in type 2 diabetes mellitus. Diabetologia. 2006;49:398–404
  70. Engler MB, Pullinger CR, Malloy MJ, Natanzon Y, Kulkarni MV, Song J, et al Genetic variation in phospholipid transfer protein modulates lipoprotein profiles in hyperalphalipoproteinemia. Metabolism. 2008;57:1719–1724
  71. Kiss RS, Kavaslar N, Okuhira K, Freeman MW, Walter S, Milne RW, et al. Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects. Arterioscler Thromb Vasc Biol. 2007;27:1139–1145
  72. Tu AY, Albers JJ. DNA sequences responsible for reduced promoter activity of human phospholipid transfer protein by fibrate. Biochem Biophys Res Commun. 1999;264:802–807
  73. Kahri J, Sane T, van Tol A, Taskinen MR. Effect of gemfibrozil on the regulation of HDL subfractions in hypertriglyceridaemic patients. J Intern Med. 1995;238:429–436
  74. Jonas A. Lecithin cholesterol acyltransferase. Biochim Biophys Acta. 2000;1529:245–256
  75. Kuivenhoven JA, Pritchard H, Hill J, Frohlich J, Assmann G, Kastelein J. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res. 1997;38:191–205
  76. Zhang K, Zhang S, Zheng K, Hou Y, Liao L, He Y, et al. Novel P143L polymorphism of the LCAT gene is associated with dyslipidemia in Chinese patients who have coronary atherosclerotic heart disease. Biochem Biophys Res Commun. 2004;318:4–10
  77. Krause BR. The Use Of LCAT Infusion To Treat Acute Coronary Syndromes. National Institutes of Health. 1–9-2008. 1–6-2009. Ref Type: Online Source.
  78. Amar MJ, Shamburek RD, Vaisman B, Knapper CL, Foger B, Hoyt RF, et al. Adenoviral expression of human lecithin-cholesterol acyltransferase in nonhuman primates leads to an antiatherogenic lipoprotein phenotype by increasing high-density lipoprotein and lowering low-density lipoprotein. Metabolism. 2009;58:568–575
  79. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272
  80. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, et al Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med. 2008;358:1240–1249
  81. Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, et al Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2009;41:56–65
  82. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, et al Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161–169

 Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

PII: S0002-9149(09)02377-7

doi: 10.1016/j.amjcard.2009.09.016

American Journal of Cardiology
Volume 104, Issue 10, Supplement , Pages 22E-31E , 16 November 2009

Article Tools

* Image Usage & Resolution