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Genetic Disorders of the Lipoprotein Metabolism; Diagnosis and Management

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Clinical Cardiogenetics

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Abstract

Atherosclerosis, leading to ischemic manifestations in different vascular beds, is the leading cause of morbidity and mortality worldwide. It is a multifactorial disease, driven by a combination of genetic, environmental, and behavioral factors. The process of atherosclerosis accelerates in the presence of classical risk factors such as dyslipidemia, hypertension, diabetes mellitus, obesity, and smoking. Dyslipidemia is one of the major contributors to atherosclerosis and includes both elevated low-density-lipoprotein cholesterol (LDL-C) levels, as well as decreased high-density-lipoprotein cholesterol (HDL-C) levels.1 The crucial role of increased plasma LDL-C levels in the pathogenesis of atherosclerosis has been well established. This also applies to the pharmacological reduction of plasma LDL-C levels accomplished by hydroxyl–methyl–glutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins. A large prospective meta-analysis including over 90,000 individuals demonstrated that a LDL-C reduction of 1 mmol/L is associated with a 21% reduction in major cardiovascular events.2 In addition, decreased plasma HDL-C levels are an independent predictor of cardiovascular disease (CVD), as has been unequivocally established by numerous epidemiological studies. Almost 40% of patients with premature CAD have low HDL-C levels, either alone or in conjunction with hypertriglyceridemia or combined hyperlipidemia.3 Furthermore, it has been estimated that each 0.03 mmol/L (1 mg/dL) increase in HDL-C is associated with a 2% reduction CAD risk in men and a 3% reduction in women.4 However, whether raising HDL-C by pharmacological means will result in cardiovascular benefit is disputable. A recent meta-regression analysis of 108 randomized controlled trials, including more than 300,000 patients using several lipid-modifying interventions, did not show a relationship between treatment-induced increases in HDL-C and a decrease in coronary heart disease events or deaths when corrected for concurrent LDL-C reductions.5 Nevertheless, this study does not prove that increasing HDL-C in selected patients with low HDL-C levels has no value.6 In addition, these studies evaluated only HDL-C concentrations and did not address HDL functionality.

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Abbreviations

ABC:

Adenosine tri-phosphate (ATP) binding cassette

ACAT:

Acyl-coenzyme A: cholesterol O-acyltransferase

ApoA1:

Apolipoprotein A1

BAS:

Bile acid sequestrants

CAD:

Coronary artery disease

CE:

Cholesterylester

CETP:

Cholesterylester transfer protein

cIMT:

Carotid intima media thickness

CHD:

Coronary heart disease

CVD:

Cardio vascular disease

FCH:

Familial combined hyperlipidemia

FD:

Familial dysbetalipoproteinemia

FDB:

Familial defective apolipoprotein B

FH:

Familial hypercholesterolemia

FHTG:

Familial hypertriglyceridemia

HDL-C:

High density lipoprotein cholesterol

HL:

Hepatic lipase

HMG-CoA:

3-Hydroxyl-3-methylglutaryl coenzyme A

IDL:

Intermediate density lipoprotein

LCAT:

Lecithin:cholesteryl acyltransferase

LDL-C:

Low density lipoprotein cholesterol

LDL-R:

Low density lipoprotein receptor

LDLRAP:

LDL-receptor adapting protein

LIPC:

Gene encoding hepatic lipase

LIPG:

Gene encoding endothelial lipase

LPL:

Lipoprotein lipase

NPC1L1:

Niemann-Pick C1 like 1

PCSK9:

Proprotein convertase subtilisin/kexin type 9

PLTP:

Phospholipid transfer protein

RCT:

Reverse cholesterol transport

SNP:

Single nucleotide polymorphism

SR-B1:

Scavenger receptor B1

TC:

Total cholesterol

VLDL:

Very low density lipoprotein

References

  1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 September 11;364(9438):937-952.

    Article  PubMed  Google Scholar 

  2. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet. 2005 October 8;366(9493):1267-1278.

    Article  PubMed  CAS  Google Scholar 

  3. Genest JJ Jr, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992 June;85(6):2025-2033.

    Article  PubMed  Google Scholar 

  4. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989 January;79(1):8-15.

    Article  PubMed  CAS  Google Scholar 

  5. Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ. 2009;338:b92.

    Article  PubMed  CAS  Google Scholar 

  6. Ghali WA, Rodondi N. HDL cholesterol and cardiovascular risk. BMJ. 2009;338:a3065.

    Article  PubMed  Google Scholar 

  7. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10, 158 incident cases among 262, 525 participants in 29 Western prospective studies. Circulation. 2007 January 30;115(4):450-458.

    Article  PubMed  CAS  Google Scholar 

  8. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk. 1996 April;3(2):213-219.

    Article  PubMed  CAS  Google Scholar 

  9. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA. 2007 July 18;298(3):309-316.

    Article  PubMed  CAS  Google Scholar 

  10. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007 July 18;298(3):299-308.

    Article  PubMed  CAS  Google Scholar 

  11. Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003 June;46(6):733-749.

    Article  PubMed  Google Scholar 

  12. Gandotra P, Miller M. The role of triglycerides in cardiovascular risk. Curr Cardiol Rep. 2008 November;10(6):505-511.

    Article  PubMed  Google Scholar 

  13. Neeli I, Siddiqi SA, Siddiqi S, et al. Liver fatty acid-binding protein initiates budding of pre-chylomicron transport vesicles from intestinal endoplasmic reticulum. J Biol Chem. 2007 June 22;282(25):17974-17984.

    Article  PubMed  CAS  Google Scholar 

  14. Davies JP, Levy B, Ioannou YA. Evidence for a Niemann-Pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics. 2000 April 15;65(2):137-145.

    Article  PubMed  CAS  Google Scholar 

  15. Graf GA, Cohen JC, Hobbs HH. Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking. J Biol Chem. 2004 June 4;279(23):24881-24888.

    Article  PubMed  CAS  Google Scholar 

  16. Temel RE, Tang W, Ma Y, et al. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest. 2007 July;117(7):1968-1978.

    Article  PubMed  CAS  Google Scholar 

  17. Grundy SM. Absorption and metabolism of dietary cholesterol. Annu Rev Nutr. 1983;3:71-96.

    Article  PubMed  CAS  Google Scholar 

  18. Beigneux AP, Davies BS, Gin P, et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 2007 April;5(4):279-291.

    Article  PubMed  CAS  Google Scholar 

  19. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 June;34(2):154-156.

    Article  PubMed  CAS  Google Scholar 

  20. Tall AR. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J Intern Med. 2008 March;263(3):256-273.

    Article  PubMed  CAS  Google Scholar 

  21. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005 June 24;96(12):1221-1232.

    Article  PubMed  CAS  Google Scholar 

  22. Van TA. Phospholipid transfer protein. Curr Opin Lipidol. 2002 April;13(2):135-139.

    Article  Google Scholar 

  23. Quagliarini F, Vallve JC, Campagna F, et al. Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene. Mol Genet Metab. 2007 November;92(3):243-248.

    Article  PubMed  CAS  Google Scholar 

  24. Garcia CK, Wilund K, Arca M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001 May 18;292(5520):1394-1398.

    Article  PubMed  CAS  Google Scholar 

  25. Leitersdorf E, Tobin EJ, Davignon J, Hobbs HH. Common low-density lipoprotein receptor mutations in the French Canadian population. J Clin Invest. 1990 April;85(4):1014-1023.

    Article  PubMed  CAS  Google Scholar 

  26. Goldstein JL, Hobbs HH, Brown MS. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001:2863-2913.

    Google Scholar 

  27. Leigh SE, Foster AH, Whittall RA, Hubbart CS, Humphries SE. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet. 2008 July;72(Pt 4):485-498.

    Article  PubMed  CAS  Google Scholar 

  28. Varret M, Abifadel M, Rabes JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008 January;73(1):1-13.

    Article  PubMed  CAS  Google Scholar 

  29. Allard D, Amsellem S, Abifadel M, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005 November;26(5):497.

    Article  PubMed  Google Scholar 

  30. Goldstein JL, Hobbs HH, Brown MS. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001:2863-2913.

    Google Scholar 

  31. Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet. 1969 December 27;2(7635):1380-1382.

    Article  PubMed  CAS  Google Scholar 

  32. Souverein OW, Defesche JC, Zwinderman AH, Kastelein JJ, Tanck MW. Influence of LDL-receptor mutation type on age at first cardiovascular event in patients with familial hypercholesterolaemia. Eur Heart J. 2007 February;28(3):299-304.

    Article  PubMed  CAS  Google Scholar 

  33. De JS, Lilien MR, Op’t RJ, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol. 2002 December 18;40(12):2117-2121.

    Article  Google Scholar 

  34. Wiegman A, De GE, Hutten BA, et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 2004 January 31;363(9406):369-370.

    Article  PubMed  Google Scholar 

  35. Huijgen R, Vissers MN, Defesche JC, Lansberg PJ, Kastelein JJ, Hutten BA. Familial hypercholesterolemia: current treatment and advances in management. Expert Rev Cardiovasc Ther. 2008 April;6(4):567-581.

    Article  PubMed  CAS  Google Scholar 

  36. Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55, 000 vascular deaths. Lancet. 2007 December 1;370(9602):1829-1839.

    Article  PubMed  CAS  Google Scholar 

  37. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008 April 3;358(14):1431-1443.

    Article  PubMed  CAS  Google Scholar 

  38. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J. 2008 November;156(5):826-832.

    Article  PubMed  CAS  Google Scholar 

  39. Florentin M, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Colesevelam hydrochloride in clinical practice: a new approach in the treatment of hypercholesterolaemia. Curr Med Res Opin. 2008 April;24(4):995-1009.

    Article  PubMed  CAS  Google Scholar 

  40. Kastelein JJ, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation. 2006 October 17;114(16):1729-1735.

    Article  PubMed  CAS  Google Scholar 

  41. Visser ME, Jakulj L, Kastelein JJ, Stroes ES. LDL-C-lowering therapy: current and future therapeutic targets. Curr Cardiol Rep. 2008 November;10(6):512-520.

    Article  PubMed  Google Scholar 

  42. Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007 August;27(8):1803-1810.

    Article  PubMed  CAS  Google Scholar 

  43. Arambepola C, Farmer AJ, Perera R, Neil HA. Statin treatment for children and adolescents with heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. Atherosclerosis. 2007 December;195(2):339-347.

    Article  PubMed  CAS  Google Scholar 

  44. Rodenburg J, Vissers MN, Wiegman A, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007 August 7;116(6):664-668.

    Article  PubMed  CAS  Google Scholar 

  45. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006 December 12;114(24):2710-2738.

    Article  PubMed  Google Scholar 

  46. Miserez AR, Muller PY. Familial defective apolipoprotein B-100: a mutation emerged in the mesolithic ancestors of Celtic peoples? Atherosclerosis. 2000 February;148(2):433-436.

    Article  PubMed  CAS  Google Scholar 

  47. Defesche JC, Pricker KL, Hayden MR, van der Ende BE, Kastelein JJ. Familial defective apolipoprotein B-100 is clinically indistinguishable from familial hypercholesterolemia. Arch Intern Med. 1993 October 25;153(20):2349-2356.

    Article  PubMed  CAS  Google Scholar 

  48. Miserez AR, Keller U. Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 1995 October;15(10):1719-1729.

    Article  PubMed  CAS  Google Scholar 

  49. Eden ER, Sun XM, Patel DD, Soutar AK. Adaptor protein disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia. Hum Mol Genet. 2007 November 15;16(22):2751-2759.

    Article  PubMed  CAS  Google Scholar 

  50. Cohen JC, Kimmel M, Polanski A, Hobbs HH. Molecular mechanisms of autosomal recessive hypercholesterolemia. Curr Opin Lipidol. 2003 April;14(2):121-127.

    Article  PubMed  CAS  Google Scholar 

  51. Wilund KR, Yi M, Campagna F, et al. Molecular mechanisms of autosomal recessive hypercholesterolemia. Hum Mol Genet. 2002 November 15;11(24):3019-3030.

    Article  PubMed  CAS  Google Scholar 

  52. Rodenburg J, Wiegman A, Vissers MN, Kastelein JJ, Stalenhoef AF. A boy with autosomal recessive hypercholesterolaemia. Neth J Med. 2004 March;62(3):89-93.

    PubMed  CAS  Google Scholar 

  53. Wierzbicki AS, Graham CA, Young IS, Nicholls DP. Familial combined hyperlipidaemia: under - defined and under - diagnosed? Curr Vasc Pharmacol. 2008 January;6(1):13-22.

    Article  PubMed  CAS  Google Scholar 

  54. Gaddi A, Cicero AF, Odoo FO, Poli AA, Paoletti R. Practical guidelines for familial combined hyperlipidemia diagnosis: an up-date. Vasc Health Risk Manag. 2007;3(6):877-886.

    PubMed  CAS  Google Scholar 

  55. Schaefer EJ, Genest JJ Jr, Ordovas JM, Salem DN, Wilson PW. Familial lipoprotein disorders and premature coronary artery disease. Atherosclerosis. 1994 August;108(Suppl):S41-S54.

    Article  PubMed  Google Scholar 

  56. Veerkamp MJ, De GJ, Hendriks JC, Demacker PN, Stalenhoef AF. Nomogram to diagnose familial combined hyperlipidemia on the basis of results of a 5-year follow-up study. Circulation. 2004 June 22;109(24):2980-2985.

    Article  PubMed  CAS  Google Scholar 

  57. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000 December 1;290(5497):1771-1775.

    Article  PubMed  CAS  Google Scholar 

  58. Lu K, Lee MH, Yu H, et al. Molecular cloning, genomic organization, genetic variations, and characterization of murine sterolin genes Abcg5 and Abcg8. J Lipid Res. 2002 April;43(4):565-578.

    PubMed  CAS  Google Scholar 

  59. Hubacek JA, Berge KE, Cohen JC, Hobbs HH. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat. 2001 October;18(4):359-360.

    Article  PubMed  CAS  Google Scholar 

  60. Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974 April;53(4):1033-1043.

    Article  PubMed  CAS  Google Scholar 

  61. Salen G, Shefer S, Nguyen L, Ness GC, Tint GS, Shore V. Sitosterolemia. J Lipid Res. 1992 July;33(7):945-955.

    PubMed  CAS  Google Scholar 

  62. Salen G, Von BK, Lutjohann D, et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation. 2004 March 2;109(8):966-971.

    Article  PubMed  CAS  Google Scholar 

  63. Salen G, Starc T, Sisk CM, Patel SB. Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis. Gastroenterology. 2006 May;130(6):1853-1857.

    Article  PubMed  Google Scholar 

  64. Wang X, Paigen B. Genetics of variation in HDL cholesterol in humans and mice. Circ Res. 2005 January 7;96(1):27-42.

    Article  PubMed  CAS  Google Scholar 

  65. Von EA. Differential diagnosis of familial high density lipoprotein deficiency syndromes. Atherosclerosis. 2006 June;186(2):231-239.

    Article  CAS  Google Scholar 

  66. Khovidhunkit W, Memon RA, Feingold KR, Grunfeld C. Infection and inflammation-induced proatherogenic changes of lipoproteins. J Infect Dis. 2000 June;181(Suppl 3):S462-S472.

    Article  PubMed  CAS  Google Scholar 

  67. Paolini JF, Mitchel YB, Reyes R, et al. Effects of laropiprant on nicotinic acid-induced flushing in patients with dyslipidemia. Am J Cardiol. 2008 March 1;101(5):625-630.

    Article  PubMed  CAS  Google Scholar 

  68. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986 December;8(6):1245-1255.

    Article  PubMed  CAS  Google Scholar 

  69. Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease – a pooled meta-analysis of long-term randomized placebo-controlled clinical trials. Am Heart J. 2007 November;154(5):943-953.

    Article  PubMed  CAS  Google Scholar 

  70. Link JJ, Rohatgi A, de Lemos JA. HDL cholesterol: physiology, pathophysiology, and management. Curr Probl Cardiol. 2007 May;32(5):268-314.

    Article  PubMed  Google Scholar 

  71. Hausenloy DJ, Yellon DM. Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels. Heart. 2008 June;94(6):706-714.

    Article  PubMed  CAS  Google Scholar 

  72. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007 November 22;357(21):2109-2122.

    Article  PubMed  CAS  Google Scholar 

  73. Forrest MJ, Bloomfield D, Briscoe RJ, 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 August;154(7):1465-1473.

    Article  PubMed  CAS  Google Scholar 

  74. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet. 2007 December 8;370(9603):1907-1914.

    Article  PubMed  CAS  Google Scholar 

  75. De Grooth GJ, Kuivenhoven JA, Stalenhoef AF, 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 May 7;105(18):2159-2165.

    Article  PubMed  CAS  Google Scholar 

  76. Kuivenhoven JA, de Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combination with pravastatin in type II dyslipidemia. Am J Cardiol. 2005 May 1;95(9):1085-1088.

    Article  PubMed  CAS  Google Scholar 

  77. Pisciotta L, Fasano T, Calabresi L, et al. A novel mutation of the apolipoprotein A-I gene in a family with familial combined hyperlipidemia. Atherosclerosis. 2008 May;198(1):145-151.

    Article  PubMed  CAS  Google Scholar 

  78. Joy T, Wang J, Hahn A, Hegele RA. APOA1 related amyloidosis: a case report and literature review. Clin Biochem. 2003 November;36(8):641-645.

    Article  PubMed  CAS  Google Scholar 

  79. Hovingh GK, Brownlie A, Bisoendial RJ, 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 October 6;44(7):1429-1435.

    Article  PubMed  CAS  Google Scholar 

  80. Gomaraschi M, Baldassarre D, Amato M, et al. Normal vascular function despite low levels of high-density lipoprotein cholesterol in carriers of the apolipoprotein A-I(Milano) mutant. Circulation. 2007 November 6;116(19):2165-2172.

    Article  PubMed  CAS  Google Scholar 

  81. Sirtori CR, Calabresi L, Franceschini G, et al. Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation. 2001 April 17;103(15):1949-1954.

    Article  PubMed  CAS  Google Scholar 

  82. Hovingh GK, De GE, der SW Van, et al. Inherited disorders of HDL metabolism and atherosclerosis. Curr Opin Lipidol. 2005 April;16(2):139-145.

    Article  PubMed  CAS  Google Scholar 

  83. 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.

    Article  PubMed  CAS  Google Scholar 

  84. Kathiresan S, Melander O, Guiducci C, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008 February;40(2):189-197.

    Article  PubMed  CAS  Google Scholar 

  85. Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008 February;40(2):161-169.

    Article  PubMed  CAS  Google Scholar 

  86. Singaraja RR, Visscher H, James ER, et al. Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro. Circ Res. 2006 August 18;99(4):389-397.

    Article  PubMed  CAS  Google Scholar 

  87. Singaraja RR, Brunham LR, Visscher H, Kastelein JJ, Hayden MR. Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol. 2003 August 1;23(8):1322-1332.

    Article  PubMed  CAS  Google Scholar 

  88. Clee SM, Kastelein JJ, Van DM, et al. Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Invest. 2000 November;106(10):1263-1270.

    Article  PubMed  CAS  Google Scholar 

  89. Van Dam MJ, De GE, Clee SM, et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study. Lancet. 2002 January 5;359(9300):37-42.

    Article  PubMed  Google Scholar 

  90. Frikke-Schmidt R, Nordestgaard BG, Stene MC, et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA. 2008 June 4;299(21):2524-2532.

    Article  PubMed  CAS  Google Scholar 

  91. Brunham LR, Singaraja RR, Duong M, et al. Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis. Arterioscler Thromb Vasc Biol. 2009 April;29(4):548-554.

    Article  PubMed  CAS  Google Scholar 

  92. Clee SM, Zwinderman AH, Engert JC, et al. Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease. Circulation. 2001 March 6;103(9):1198-1205.

    Article  PubMed  CAS  Google Scholar 

  93. Zwarts KY, Clee SM, Zwinderman AH, et al. ABCA1 regulatory variants influence coronary artery disease independent of effects on plasma lipid levels. Clin Genet. 2002 February;61(2):115-125.

    Article  PubMed  CAS  Google Scholar 

  94. Brunham LR, Kastelein JJ, Hayden MR. ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease. JAMA. 2008 November 5;300(17):1997-1998.

    Article  PubMed  Google Scholar 

  95. Kiss RS, Kavaslar N, Okuhira K, et al. Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects. Arterioscler Thromb Vasc Biol. 2007 May;27(5):1139-1145.

    Article  PubMed  CAS  Google Scholar 

  96. Ayyobi AF, McGladdery SH, Chan S, John Mancini GB, Hill JS, Frohlich JJ. Lecithin: cholesterol acyltransferase (LCAT) deficiency and risk of vascular disease: 25 year follow-up. Atherosclerosis. 2004 December;177(2): 361-366.

    Article  PubMed  CAS  Google Scholar 

  97. Shah PK. Inhibition of CETP as a novel therapeutic strategy for reducing the risk of atherosclerotic disease. Eur Heart J. 2007 January;28(1):5-12.

    Article  PubMed  CAS  Google Scholar 

  98. Tsai MY, Johnson C, Kao WH, et al. Cholesteryl ester transfer protein genetic polymorphisms, HDL cholesterol, and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2008 October;200(2):359-367.

    Article  PubMed  CAS  Google Scholar 

  99. Inazu A, Brown ML, Hesler CB, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990 November 1;323(18):1234-1238.

    Article  PubMed  CAS  Google Scholar 

  100. Inazu A, Jiang XC, Haraki T, 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 November;94(5):1872-1882.

    Article  PubMed  CAS  Google Scholar 

  101. Klerkx AH, de Grooth GJ, Zwinderman AH, Jukema JW, Kuivenhoven JA, Kastelein JJ. Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur J Clin Invest. 2004 January;34(1):21-28.

    Article  PubMed  CAS  Google Scholar 

  102. Smilde TJ, Van WS, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet. 2001 February 24;357(9256):577-581.

    Article  PubMed  CAS  Google Scholar 

  103. Boekholdt SM, Kuivenhoven JA, Wareham NJ, et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study. Circulation. 2004 September 14;110(11):1418-1423.

    Article  PubMed  CAS  Google Scholar 

  104. Gerholm-Larsen B, Tybjaerg-Hansen A, Schnohr P, Steffensen R, Nordestgaard BG. Common cholesteryl ester transfer protein mutations, decreased HDL cholesterol, and possible decreased risk of ischemic heart disease: the Copenhagen City Heart Study. Circulation. 2000 October 31;102(18):2197-2203.

    Article  Google Scholar 

  105. Curb JD, Abbott RD, Rodriguez BL, et al. 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 May;45(5):948-953.

    Article  PubMed  CAS  Google Scholar 

  106. Moriyama Y, Okamura T, Inazu A, 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 September;27(5 Pt 1):659-667.

    Article  PubMed  CAS  Google Scholar 

  107. Thompson A, Di AE, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA. 2008 June 18;299(23):2777-2788.

    Article  PubMed  CAS  Google Scholar 

  108. van Acker BA, Botma GJ, Zwinderman AH, 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 September;200(1):161-167.

    Article  PubMed  CAS  Google Scholar 

  109. Mukherjee M, Shetty KR. Variations in high-density lipoprotein cholesterol in relation to physical activity and Taq 1B polymorphism of the cholesteryl ester transfer protein gene. Clin Genet. 2004 May;65(5):412-418.

    Article  PubMed  CAS  Google Scholar 

  110. Beigneux AP, Franssen R, Bensadoun A, Gin P, Melford K, Peter J, Walzem RL, Weinstein MM, Davies BS, Kuivenhoven JA, Kastelein JJ, Fong LG, linga-Thie GM, Young SG. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler Thromb Vasc Biol. 2009 March 19;29:956–962.

    Google Scholar 

  111. Brunzell JD. Clinical practice. Hypertriglyceridemia. N Engl J Med. 2007 September 6;357(10):1009-1017.

    Article  PubMed  CAS  Google Scholar 

  112. Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2005 January 18;45(2):185-197.

    Article  PubMed  CAS  Google Scholar 

  113. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 July 13;110(2):227-239.

    Article  PubMed  Google Scholar 

  114. McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med. 2004 April 12;164(7):697-705.

    Article  PubMed  CAS  Google Scholar 

  115. Harris WS, Ginsberg HN, Arunakul N, et al. Safety and efficacy of Omacor in severe hypertriglyceridemia. J Cardiovasc Risk. 1997 October;4(5–6):385-391.

    Article  PubMed  CAS  Google Scholar 

  116. Hopper L, Ness A, Higgins JP, Moore T, Ebrahim S. GISSI-prevenzione trial. Lancet. 1999 October 30;354(9189):1557.

    Article  PubMed  CAS  Google Scholar 

  117. Merkel M, Eckel RH, Goldberg IJ. Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res. 2002 December;43(12):1997-2006.

    Article  PubMed  CAS  Google Scholar 

  118. Wang J, Cao H, Ban MR, et al. Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650). Arterioscler Thromb Vasc Biol. 2007 November;27(11):2450-2455.

    Article  PubMed  CAS  Google Scholar 

  119. Lam CW, Yuen YP, Cheng WF, Chan YW, Tong SF. Missense mutation Leu72Pro located on the carboxyl terminal amphipathic helix of apolipoprotein C-II causes familial chylomicronemia syndrome. Clin Chim Acta. 2006 February;364(1–2):256-259.

    Article  PubMed  CAS  Google Scholar 

  120. Benlian P, De Gennes JL, Foubert L, Zhang H, Gagne SE, Hayden M. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. N Engl J Med. 1996 September 19;335(12):848-854.

    Article  PubMed  CAS  Google Scholar 

  121. Saika Y, Sakai N, Takahashi M, et al. Novel LPL mutation (L303F) found in a patient associated with coronary artery disease and severe systemic atherosclerosis. Eur J Clin Invest. 2003 March;33(3):216-222.

    Article  PubMed  CAS  Google Scholar 

  122. Connelly PW, Maguire GF, Little JA. Apolipoprotein CIISt. Michael. Familial apolipoprotein CII deficiency associated with premature vascular disease. J Clin Invest. 1987 December;80(6):1597-1606.

    Article  PubMed  CAS  Google Scholar 

  123. Stroes ES, Nierman MC, Meulenberg JJ, et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol. 2008 December;28(12):2303-2304.

    Article  PubMed  CAS  Google Scholar 

  124. Franssen R, Visser ME, Kuivenhoven JA, Kastelein JJP, Dallinga-Thie GM, Stroes ESG. Role of lipoprotein lipase in triglyceride metabolism: potential therapeutic target. Future Lipidol. 2008;3(4):385-397.

    Article  CAS  Google Scholar 

  125. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007 April 10;176(8):1113-1120.

    Article  PubMed  Google Scholar 

  126. Smelt A, de Beer F. Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects. Semin Vasc Med. 2009;4(3):249-257.

    Article  Google Scholar 

  127. Walden CC, Hegele RA. Apolipoprotein E in hyperlipidemia. Ann Intern Med. 1994 June 15;120(12):1026-1036.

    Article  PubMed  CAS  Google Scholar 

  128. Wang J, Hegele RA. Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650). Lipids Health Dis. 2007;6:23.

    Article  PubMed  CAS  Google Scholar 

  129. Gin P, Beigneux AP, Davies B, et al. Normal binding of lipoprotein lipase, chylomicrons, and apo-AV to GPIHBP1 containing a G56R amino acid substitution. Biochim Biophys Acta. 2007 December;1771(12):1464-1468.

    Article  PubMed  CAS  Google Scholar 

  130. Peterfy M, Ben-Zeev O, Mao HZ, et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat Genet. 2007 December;39(12):1483-1487.

    Article  PubMed  CAS  Google Scholar 

  131. Kooner JS, Chambers JC, Guilar-Salinas CA, et al. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 2008 February;40(2):149-151.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, room F4-159.2, 1105 AZ, Amsterdam, The Netherlands

    J. J. P. Kastelein

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  1. A. Bakker
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  2. L. Jakulj
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  1. University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, 3508 GA, Netherlands

    H.F. Baars

  2. University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, 3508 GA, Netherlands

    P.A.F.M. Doevendans

  3. University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, 3508 GA, Netherlands

    J.J. van der Smagt

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Bakker, A., Jakulj, L., Kastelein, J.J.P. (2011). Genetic Disorders of the Lipoprotein Metabolism; Diagnosis and Management. In: Baars, H., Doevendans, P., van der Smagt, J. (eds) Clinical Cardiogenetics. Springer, London. https://doi.org/10.1007/978-1-84996-471-5_20

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