Skip to main content
SpringerLink
Log in

Genetic Disorders of Lipoprotein Metabolism

  • Chapter
  • First Online:
Therapeutic Lipidology

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 1169 Accesses

Abstract

Disorders of lipoprotein metabolism lead to atherosclerotic cardiovascular disease (ASCVD) and its clinical manifestations as well as other disorders such as pancreatitis. Blood lipid concentrations, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), have been shown to be highly heritable. It is estimated that at least half of the variation in serum lipids between individuals can be explained by genetic variation. While some genetic lipid disorders are associated with increased risk of ASCVD, others result in reduced ASCVD risk. This chapter summarizes the prevalence, genetics, pathophysiology, clinical presentation, diagnosis, and treatments for diseases that primarily affect LDL (familial hypercholesterolemia, autosomal recessive hypercholesterolemia, and hereditary sitosterolemia), diseases that lead to elevated TG (familial combined hyperlipidemia, familial hypertriglyceridemia, familial dysbetalipoproteinemia, and familial chylomicronemia syndrome), diseases that lead to low HDL (familial hypoalphalipoproteinemia, complete and partial familial lecithin:cholesterol acyltransferase deficiency, and ApoA1 Milano), and diseases causing low LDL (abetalipoproteinemia, familial hypobetalipoproteinemia, loss-of-function proprotein convertase subtilisin kexin type 9 mutations, and chylomicron retention disease). The genetics, structure, and function of lipoprotein (a), and its association with ASCVD are also covered. The reader should keep in mind that in patients with underlying genetic lipid disorders, the phenotype can appear atypical if other superimposed disorders are present such as diabetes, metabolic syndrome, or use of medications that can affect lipids. Consideration of these factors can help with diagnosis when the presentation of a genetic dyslipidemia appears to be atypical.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    This section was previously published as a full chapter in Chyzhyk V, Brown AS. Familial chylomicronemia syndrome: A rare but devastating autosomal recessive disorder characterized by refractory hypertriglyceridemia and recurrent pancreatitis. Trends Cardiovasc Med. 2020 Feb;30:80-5. With permission from Elsevier.

References

  1. Wierzbicki AS, Humphries SE, Minhas R, Guideline DG. Familial hypercholesterolaemia: summary of NICE guidance. BMJ. 2008;337:a1095.

    Article  PubMed  Google Scholar 

  2. Writing Group Members RVL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke statistics--2011 Update. Circulation. 2011;123:459–63.

    Google Scholar 

  3. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34–47.

    Article  CAS  PubMed  Google Scholar 

  4. Soutar AK, Naoumova RP. Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med. 2007;4:214–25.

    Article  CAS  PubMed  Google Scholar 

  5. Quagliarini F, Vallve JC, Campagna F, Alvaro A, Fuentes-Jimenez FJ, Sirinian MI, Meloni F, Masana L, Arca M. Autosomal recessive hypercholesterolemia in Spanish kindred due to a large deletion in the ARH gene. Mol Genet Metab. 2007;92:243–8.

    Article  CAS  PubMed  Google Scholar 

  6. Godard B, ten Kate L, Evers-Kiebooms G, Ayme S. Population genetic screening programmes: principles, techniques, practices, and policies. Eur J Hum Genet. 2003;11(Suppl 2):S49–87.

    Article  PubMed  Google Scholar 

  7. Goldstein JL, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973;52:1544–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Williams RR, Hopkins PN, Hunt SC, Wu LL, Hasstedt SJ, Lalouel JM, Ash KO, Stults BM, Kuida H. Population-based frequency of dyslipidemia syndromes in coronary-prone families in Utah. Arch Intern Med. 1990;150:582–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bhatnagar D, Morgan J, Siddiq S, Mackness MI, Miller JP, Durrington PN. Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. BMJ. 2000;321:1497–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. National Institute for Health and Clinical Excellence. Clinical guidelines and evidence review for familial hypercholesterolemias: the identification and management of adults and children with familial hypercholesterolemia. (Clinical Guidelines 71). 2008.

    Google Scholar 

  11. Steyn K, Goldberg YP, Kotze MJ, Steyn M, Swanepoel AS, Fourie JM, Coetzee GA, Van der Westhuyzen DR. Estimation of the prevalence of familial hypercholesterolaemia in a rural Afrikaner community by direct screening for three Afrikaner founder low density lipoprotein receptor gene mutations. Hum Genet. 1996;98:479–84.

    Article  CAS  PubMed  Google Scholar 

  12. E. A. S. Familial Hypercholesterolaemia Studies Collaboration, Vallejo-Vaz AJ, Akram A, Kondapally Seshasai SR, Cole D, Watts GF, Hovingh GK, Kastelein JJ, Mata P, et al. Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration. Atheroscler Suppl. 2016;22:1–32.

    Google Scholar 

  13. de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and nutrition examination surveys (NHANES). Circulation. 2016;133:1067–72.

    Article  PubMed  CAS  Google Scholar 

  14. Pang J, Poulter EB, Bell DA, Bates TR, Jefferson VL, Hillis GS, Schultz CJ, Watts GF. Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit. J Clin Lipidol. 2015;9:703–8.

    Article  PubMed  Google Scholar 

  15. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478–90a.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Varret M, Abifadel M, Rabes JP, Boileau C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008;73:1–13.

    Article  CAS  PubMed  Google Scholar 

  17. Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, Grundy SM, Friedl W, Davignon J, McCarthy BJ. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res. 1990;31:1337–49.

    Article  CAS  PubMed  Google Scholar 

  18. Boren J, Ekstrom U, Agren B, Nilsson-Ehle P, Innerarity TL. The molecular mechanism for the genetic disorder familial defective apolipoprotein B100. J Biol Chem. 2001;276:9214–8.

    Article  CAS  PubMed  Google Scholar 

  19. Whitfield AJ, Barrett PH, van Bockxmeer FM, Burnett JR. Lipid disorders and mutations in the APOB gene. Clin Chem. 2004;50:1725–32.

    Article  CAS  PubMed  Google Scholar 

  20. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci. 2007;32:71–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50(Suppl):S172–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science. 2001;292:1394–8.

    Article  CAS  PubMed  Google Scholar 

  23. Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC, Hovingh GK. Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ Res. 2014;115:552–5.

    Article  CAS  PubMed  Google Scholar 

  24. Goldstein JL, Hazzard WR, Schrott HG, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease. I. Lipid levels in 500 survivors of myocardial infarction. J Clin Invest. 1973;52:1533–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Watts GF, Lewis B, Sullivan DR. Familial hypercholesterolemia: a missed opportunity in preventive medicine. Nat Clin Pract Cardiovasc Med. 2007;4:404–5.

    Article  PubMed  Google Scholar 

  26. Marks D, Thorogood M, Neil HA, Humphries SE. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis. 2003;168:1–14.

    Article  CAS  PubMed  Google Scholar 

  27. Kwiterovich PO Jr. Recognition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab. 2008;93:4200–9.

    Article  CAS  PubMed  Google Scholar 

  28. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Defesche JC, Gidding SS, Harada-Shiba M, Hegele RA, Santos RD, Wierzbicki AS. Familial hypercholesterolaemia. Nat Rev Dis Primers. 2017;3:17093.

    Article  PubMed  Google Scholar 

  30. Landrum MJ, Lee JM, Benson M, Brown G, Chao C, Chitipiralla S, Gu B, Hart J, Hoffman D, et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862–8.

    Article  CAS  PubMed  Google Scholar 

  31. Goldstein JL, Brown MS. The LDL receptor locus and the genetics of familial hypercholesterolemia. Annu Rev Genet. 1979;13:259–89.

    Article  CAS  PubMed  Google Scholar 

  32. Pocovi M, Civeira F, Alonso R, Mata P. Familial hypercholesterolemia in Spain: case-finding program, clinical and genetic aspects. Semin Vasc Med. 2004;4:67–74.

    Article  PubMed  Google Scholar 

  33. Etxebarria A, Palacios L, Stef M, Tejedor D, Uribe KB, Oleaga A, Irigoyen L, Torres B, Ostolaza H, Martin C. Functional characterization of splicing and ligand-binding domain variants in the LDL receptor. Hum Mutat. 2012;33:232–43.

    Article  CAS  PubMed  Google Scholar 

  34. Ho CK, Musa FR, Bell C, Walker SW. LDLR gene synonymous mutation c.1813C>T results in mRNA splicing variation in a kindred with familial hypercholesterolaemia. Ann Clin Biochem. 2015;52:680–4.

    Article  CAS  PubMed  Google Scholar 

  35. Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet. 1990;24:133–70.

    Article  CAS  PubMed  Google Scholar 

  36. Fernandez-Higuero JA, Benito-Vicente A, Etxebarria A, Milicua JC, Ostolaza H, Arrondo JL, Martin C. Structural changes induced by acidic pH in human apolipoprotein B-100. Sci Rep. 2016;6:36324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dron JS, Hegele RA. Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants. Curr Opin Lipidol. 2017;28:161–9.

    Article  CAS  PubMed  Google Scholar 

  38. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    Article  CAS  PubMed  Google Scholar 

  39. Koivisto UM, Hamalainen L, Taskinen MR, Kettunen K, Kontula K. Prevalence of familial hypercholesterolemia among young north Karelian patients with coronary heart disease: a study based on diagnosis by polymerase chain reaction. J Lipid Res. 1993;34:269–77.

    Article  CAS  PubMed  Google Scholar 

  40. Rallidis LS, Lekakis J, Panagiotakos D, Fountoulaki K, Komporozos C, Apostolou T, Rizos I, Kremastinos DT. Long-term prognostic factors of young patients (<or = 35 years) having acute myocardial infarction: the detrimental role of continuation of smoking. Eur J Cardiovasc Prev Rehabil. 2008;15:567–71.

    Article  PubMed  Google Scholar 

  41. Gaudet D, Vohl MC, Julien P, Tremblay G, Perron P, Gagne C, Bergeron J, Moorjani S, Despres JP. Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians. Am J Cardiol. 1998;82:299–305.

    Article  CAS  PubMed  Google Scholar 

  42. Junyent M, Gilabert R, Jarauta E, Nunez I, Cofan M, Civeira F, Pocovi M, Mallen M, Zambon D, et al. Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia. Atherosclerosis. 2010;208:437–41.

    Article  CAS  PubMed  Google Scholar 

  43. Daniels SR, Greer FR. Committee on N. lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122:198–208.

    Article  PubMed  Google Scholar 

  44. Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, Hopkins PN. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72:171–6.

    Article  CAS  PubMed  Google Scholar 

  45. Centers for Disease C, Prevention. Vital signs: prevalence, treatment, and control of high levels of low-density lipoprotein cholesterol--United States, 1999-2002 and 2005-200. MMWR Morb Mortal Wkly Rep. 2011;60:109–14.

    Google Scholar 

  46. Beeharry D, Coupe B, Benbow EW, Morgan J, Kwok S, Charlton-Menys V, France M, Durrington PN. Familial hypercholesterolaemia commonly presents with Achilles tenosynovitis. Ann Rheum Dis. 2006;65:312–5.

    Article  CAS  PubMed  Google Scholar 

  47. National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. 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) final report. Circulation. 2002;106:3143–421.

    Google Scholar 

  48. Carmena R, Roy M, Roederer G, Minnich A, Davignon J. Coexisting dysbetalipoproteinemia and familial hypercholesterolemia. Clinical and laboratory observations. Atherosclerosis. 2000;148:113–24.

    Article  CAS  PubMed  Google Scholar 

  49. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290:1771–5.

    Article  CAS  PubMed  Google Scholar 

  50. Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab. 1973;15:132–40.

    Article  CAS  PubMed  Google Scholar 

  51. Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, Harrison SC, Li K, Drenos F, et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013;381:1293–301.

    Article  CAS  PubMed  Google Scholar 

  52. Civeira F. International panel on Management of Familial H. guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004;173:55–68.

    Article  CAS  PubMed  Google Scholar 

  53. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991;303:893–6.

    Google Scholar 

  54. Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004;66:483–7.

    Article  CAS  PubMed  Google Scholar 

  55. Herman K, Van Heyningen C, Wile D. Cascae screening for familial hypercholestroleaemia and its effectiveness in the prevention of vascular disease. Br J Diabetes Vasc Dis. 2009;9:171–4.

    Article  Google Scholar 

  56. Hopkins PN, Toth PP, Ballantyne CM, Rader DJ. National Lipid Association Expert Panel on familial H. familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:S9–17.

    Article  PubMed  Google Scholar 

  57. Robinson JG, Goldberg AC. National Lipid Association Expert Panel on familial H. treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:S18–29.

    Article  PubMed  Google Scholar 

  58. Ito MK, McGowan MP, Moriarty PM. National Lipid Association Expert Panel on familial H. management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:S38–45.

    Article  PubMed  Google Scholar 

  59. Hopkins PN. Encouraging appropriate treatment for familial hypercholesterolemia. Clinical Lipidology. 2010;5:339–54.

    Article  Google Scholar 

  60. Perez de Isla L, Alonso R, Watts GF, Mata N, Saltijeral Cerezo A, Muniz O, Fuentes F, Diaz-Diaz JL, de Andres R, et al. Attainment of LDL-Cholesterol Treatment Goals in Patients With Familial Hypercholesterolemia: 5-Year SAFEHEART Registry Follow-Up. J Am Coll Cardiol. 2016;67:1278–85.

    Google Scholar 

  61. Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J. 2008;29:2625–33.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39.

    Article  PubMed  Google Scholar 

  63. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA study): a prospective randomised controlled trial. Lancet. 2006;368:1155–63.

    Article  CAS  PubMed  Google Scholar 

  64. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.

    Google Scholar 

  65. Lambert M, Lupien PJ, Gagne C, Levy E, Blaichman S, Langlois S, Hayden M, Rose V, Clarke JT, et al. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian lovastatin in children study group. Pediatrics. 1996;97:619–28.

    Article  CAS  PubMed  Google Scholar 

  66. Firth JC, Marais AD, Byrnes P, Fusco RA, Bonnici F. Fluvastatin in heterozygous familial hypercholesterolemia. Cardiol Young. 2000;10:35.

    Google Scholar 

  67. McCrindle BW, Urbina EM, Dennison BA, Jacobson MS. Steinberger J, Rocchini AP, Hayman LL, Daniels SR, American Heart Association atherosclerosis H, et al. drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association atherosclerosis, hypertension, and obesity in youth committee, Council of Cardiovascular Disease in the Young, with the council on cardiovascular nursing. Circulation. 2007;115:1948–67.

    Article  PubMed  Google Scholar 

  68. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–92.

    Article  CAS  PubMed  Google Scholar 

  69. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.

    Article  CAS  PubMed  Google Scholar 

  70. Gagne C, Gaudet D, Bruckert E, Ezetimibe SG. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation. 2002;105:2469–75.

    Article  CAS  PubMed  Google Scholar 

  71. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, Visseren FL, Sijbrands EJ, Trip MD, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358:1431–43.

    Article  CAS  PubMed  Google Scholar 

  72. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22.

    Article  CAS  PubMed  Google Scholar 

  73. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107.

    Article  CAS  PubMed  Google Scholar 

  74. Huijgen R, Abbink EJ, Bruckert E, Stalenhoef AF, Imholz BP, Durrington PN, Trip MD, Eriksson M, Visseren FL, et al. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther. 2010;32:615–25.

    Article  CAS  PubMed  Google Scholar 

  75. Perry CM. Colesevelam: in pediatric patients with heterozygous familial hypercholesterolemia. Paediatr Drugs. 2010;12:133–40.

    Article  PubMed  Google Scholar 

  76. Jacobson TA. Myopathy with statin-fibrate combination therapy: clinical considerations. Nat Rev Endocrinol. 2009;5:507–18.

    Article  CAS  PubMed  Google Scholar 

  77. Morgan JM, Capuzzi DM, Guyton JR. A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients. Am J Cardiol. 1998;82:29U–34U; discussion 9U-41U.

    Google Scholar 

  78. Thompson GR. LDL apheresis. Atherosclerosis. 2003;167:1–13.

    Article  CAS  PubMed  Google Scholar 

  79. Gordon BR, Kelsey SF, Dau PC, Gotto AM Jr, Graham K, Illingworth DR, Isaacsohn J, Jones PH, Leitman SF, et al. Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Liposorber study group. Am J Cardiol. 1998;81:407–11.

    Article  CAS  PubMed  Google Scholar 

  80. Bambauer R. Is lipoprotein (a)-apheresis useful? Ther Apher Dial. 2005;9:142–7.

    Article  CAS  PubMed  Google Scholar 

  81. D'Erasmo L, Minicocci I, Nicolucci A, Pintus P. Roeters Van Lennep JE, Masana L, Mata P, Sanchez-Hernandez RM, Prieto-Matos P, et al. autosomal recessive hypercholesterolemia: long-term cardiovascular outcomes. J Am Coll Cardiol. 2018;71:279–88.

    CAS  PubMed  Google Scholar 

  82. Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol. 2001;12:141–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ajagbe BO, Othman RA, Myrie SB. Plant sterols, Stanols, and Sitosterolemia. J AOAC Int. 2015;98:716–23.

    Article  CAS  PubMed  Google Scholar 

  84. Brouwers MC, van Greevenbroek MM, Stehouwer CD, de Graaf J, Stalenhoef AF. The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol. 2012;8:352–62.

    Article  CAS  PubMed  Google Scholar 

  85. Bello-Chavolla OY, Kuri-Garcia A, Rios-Rios M, Vargas-Vazquez A, Cortes-Arroyo JE, Tapia-Gonzalez G, Cruz-Bautista I, Aguilar-Salinas CA. Familial combined hyperlipidemia: current knowledge, perspectives, and controversies. Rev Investig Clin. 2018;70:224–36.

    CAS  Google Scholar 

  86. Ripatti P, Ramo JT, Soderlund S, Surakka I, Matikainen N, Pirinen M, Pajukanta P, Sarin AP, Service SK, et al. The contribution of GWAS loci in familial dyslipidemias. PLoS Genet. 2016;12:e1006078.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. van Greevenbroek MM, Stalenhoef AF, de Graaf J, Brouwers MC. Familial combined hyperlipidemia: from molecular insights to tailored therapy. Curr Opin Lipidol. 2014;25:176–82.

    Article  PubMed  CAS  Google Scholar 

  88. Brouwers MC, de Graaf J, van Greevenbroek MM, Schaper N, Stehouwer CD, Stalenhoef AF. Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus. Curr Opin Lipidol. 2010;21:530–8.

    Article  CAS  PubMed  Google Scholar 

  89. Sahebkar A, Watts GF. New therapies targeting apoB metabolism for high-risk patients with inherited dyslipidaemias: what can the clinician expect? Cardiovasc Drugs Ther. 2013;27:559–67.

    Article  CAS  PubMed  Google Scholar 

  90. Brahm AJ, Hegele RA. Combined hyperlipidemia: familial but not (usually) monogenic. Curr Opin Lipidol. 2016;27:131–40.

    Article  CAS  PubMed  Google Scholar 

  91. Kei AA, Filippatos TD, Tsimihodimos V, Elisaf MS. A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease. Metabolism. 2012;61:906–21.

    Article  CAS  PubMed  Google Scholar 

  92. Martin SS, Abd TT, Jones SR, Michos ED, Blumenthal RS, Blaha MJ. 2013 ACC/AHA cholesterol treatment guideline: what was done well and what could be done better. J Am Coll Cardiol. 2014;63:2674–8.

    Article  PubMed  Google Scholar 

  93. Arca M, Montali A, Pigna G, Antonini R, Antonini TM, Luigi P, Fraioli A, Mastrantoni M, Maddaloni M, Letizia C. Comparison of atorvastatin versus fenofibrate in reaching lipid targets and influencing biomarkers of endothelial damage in patients with familial combined hyperlipidemia. Metabolism. 2007;56:1534–41.

    Article  CAS  PubMed  Google Scholar 

  94. Daniels S, Couch S. Lipid disorders in children. In: Pediatric Endocrinology. 4th ed; 2014. p. 1015–34.

    Chapter  Google Scholar 

  95. Mahley RW, Rall SC Jr. Type III hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In: Scriver CR, Sly SW, Valle D, editors. The metabolic and molecular basis of inherited disease. 7th ed. New York: McGraw-Hill; 1995. p. 1953–80.

    Google Scholar 

  96. Mahley RW, Huang Y, Rall SC Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res. 1999;40:1933–49.

    Article  CAS  PubMed  Google Scholar 

  97. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–30.

    Article  CAS  PubMed  Google Scholar 

  98. Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, et al. Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA. 2007;298:1300–11.

    Article  CAS  PubMed  Google Scholar 

  99. Huang Y, Liu XQ, Rall SC Jr, Taylor JM, von Eckardstein A, Assmann G, Mahley RW. Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem. 1998;273:26388–93.

    Article  CAS  PubMed  Google Scholar 

  100. Zannis VI. Genetic polymorphism in human apolipoprotein E. Methods Enzymol. 1986;128:823–51.

    Article  CAS  PubMed  Google Scholar 

  101. Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999;40:1–16.

    Article  CAS  PubMed  Google Scholar 

  102. Dong LM, Parkin S, Trakhanov SD, Rupp B, Simmons T, Arnold KS, Newhouse YM, Innerarity TL, Weisgraber KH. Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia. Nat Struct Biol. 1996;3:718–22.

    Article  CAS  PubMed  Google Scholar 

  103. Mahley RW. Atherogenic lipoproteins and coronary artery disease: concepts derived from recent advances in cellular and molecular biology. Circulation. 1985;72:943–8.

    Article  CAS  PubMed  Google Scholar 

  104. Mahley RW, Weisgraber KH, Innerarity TL, Rall SC Jr. Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism. JAMA. 1991;265:78–83.

    Article  CAS  PubMed  Google Scholar 

  105. Mahley RW, Weisgraber KH, Farese RV Jr. Disorders of lipid metabolism. In: Williams RH, Wilson JD, editors. Williams textbook of endocrinology. Philadelphia: W.B. Saunders; 1998. p. 1099–153.

    Google Scholar 

  106. Dose J, Huebbe P, Nebel A, Rimbach G. APOE genotype and stress response - a mini review. Lipids Health Dis. 2016;15:121.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Thuren T, Weisgraber KH, Sisson P, Waite M. Role of apolipoprotein E in hepatic lipase catalyzed hydrolysis of phospholipid in high-density lipoproteins. Biochemistry. 1992;31:2332–8.

    Article  CAS  PubMed  Google Scholar 

  108. Kuipers F, Jong MC, Lin Y, Eck M, Havinga R, Bloks V, Verkade HJ, Hofker MH, Moshage H, et al. Impaired secretion of very low density lipoprotein-triglycerides by apolipoprotein E- deficient mouse hepatocytes. J Clin Invest. 1997;100:2915–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sniderman A, Tremblay A, Bergeron J, Gagne C, Couture P. Diagnosis of type III hyperlipoproteinemia from plasma total cholesterol, triglyceride, and apolipoprotein B. J Clin Lipidol. 2007;1:256–63.

    Article  PubMed  Google Scholar 

  110. de Graaf J, Couture P, Sniderman A. A diagnostic algorithm for the atherogenic apolipoprotein B dyslipoproteinemias. Nat Clin Pract Endocrinol Metab. 2008;4:608–18.

    Article  PubMed  CAS  Google Scholar 

  111. Sniderman AD, de Graaf J, Thanassoulis G, Tremblay AJ, Martin SS, Couture P. The spectrum of type III hyperlipoproteinemia. J Clin Lipidol. 2018;12:1383–9.

    Google Scholar 

  112. Brunzell JD. Genetic dyslipidemia. Clinical Lipidology: a companion to Branwald's heart disease. Philadelphia: Elsevier; 2010. p. 71–84.

    Google Scholar 

  113. Blom DJ, Byrnes P, Jones S, Marais AD. Dysbetalipoproteinaemia--clinical and pathophysiological features. S Afr Med J. 2002;92:892–7.

    CAS  PubMed  Google Scholar 

  114. Cruz PD Jr, East C, Bergstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. 1988;19:95–111.

    Article  PubMed  Google Scholar 

  115. Koopal C, Marais AD, Visseren FL. Familial dysbetalipoproteinemia: an underdiagnosed lipid disorder. Curr Opin Endocrinol Diabetes Obes. 2017;24:133–9.

    Article  CAS  PubMed  Google Scholar 

  116. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176:1113–20.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Morganroth J, Levy RI, Fredrickson DS. The biochemical, clinical, and genetic features of type III hyperlipoproteinemia. Ann Intern Med. 1975;82:158–74.

    Article  CAS  PubMed  Google Scholar 

  118. Marais AD. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology. 2019;51:165–76.

    Article  CAS  PubMed  Google Scholar 

  119. Blom DJ, O'Neill FH, Marais AD. Screening for dysbetalipoproteinemia by plasma cholesterol and apolipoprotein B concentrations. Clin Chem. 2005;51:904–7.

    Article  CAS  PubMed  Google Scholar 

  120. Murase T, Okubo M, Takeuchi I. Non-HDL-cholesterol/apolipoprotein B ratio: a useful distinguishing feature in the screening for type III hyperlipoproteinemia. J Clin Lipidol. 2010;4:99–104.

    Article  PubMed  Google Scholar 

  121. Ferrier D. Lippincott illustrated reviews: biochemistry: Wolters Kluwer Health, Inc; 2017.

    Google Scholar 

  122. Hazzard WR, Porte D Jr, Bierman EL. Abnormal lipid composition of very low density lipoproteins in diagnosis of broad-beta disease (type 3 hyperlipoproteinemia). Metabolism. 1972;21:1009–19.

    Article  CAS  PubMed  Google Scholar 

  123. Masket BH, Levy RI, Fredrickson DS. The use of polyacrylamide gel electrophoresis in differentiating type 3 hyperlipoproteinemia. J Lab Clin Med. 1973;81:794–802.

    CAS  PubMed  Google Scholar 

  124. Blom DJ, Byrnes P, Jones S, Marais AD. Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia. J Lipid Res. 2003;44:212–7.

    Article  CAS  PubMed  Google Scholar 

  125. Rader DJ, Kathiresan S. Lipoprotein disorders. In: Ginsburg GS, Willard HF, editors. Genomic and precision medicine. Boston: Academic Press; 2018. p. 27–46.

    Chapter  Google Scholar 

  126. Seip RL, Otvos J, Bilbie C, Tsongalis GJ, Miles M, Zoeller R, Visich P, Gordon P, Angelopoulos TJ, et al. The effect of apolipoprotein E genotype on serum lipoprotein particle response to exercise. Atherosclerosis. 2006;188:126–33.

    Article  CAS  PubMed  Google Scholar 

  127. Feussner G, Eichinger M, Ziegler R. The influence of simvastatin alone or in combination with gemfibrozil on plasma lipids and lipoproteins in patients with type III hyperlipoproteinemia. Clin Investig. 1992;70:1027–35.

    Article  CAS  PubMed  Google Scholar 

  128. Illingworth DR, O'Malley JP. The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia. Metabolism. 1990;39:403–9.

    Article  CAS  PubMed  Google Scholar 

  129. Gylling H, Relas H, Miettinen TA. Postprandial vitamin a and squalene clearances and cholesterol synthesis off and on lovastatin treatment in type III hyperlipoproteinemia. Atherosclerosis. 1995;115:17–26.

    Article  CAS  PubMed  Google Scholar 

  130. Reyes-Soffer G, Ngai CI, Lovato L, Karmally W, Ramakrishnan R, Holleran S, Ginsberg HN. Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial. Diabetes Care. 2013;36:422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Guyton JR. Treatment of type III hyperlipoproteinemia. Am Heart J. 1999;138:17–8.

    Article  CAS  PubMed  Google Scholar 

  132. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, et al. 2016 ESC/EAS guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37:2999–3058.

    Article  PubMed  Google Scholar 

  133. Buckley R, Shewring B, Turner R, Yaqoob P, Minihane AM. Circulating triacylglycerol and apoE levels in response to EPA and docosahexaenoic acid supplementation in adult human subjects. Br J Nutr. 2004;92:477–83.

    Article  CAS  PubMed  Google Scholar 

  134. Adiels M, Chapman MJ, Robillard P, Krempf M, Laville M, Boren J, Niacin Study G. Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: insights from metabolic biomarker profiling and network analysis. J Clin Lipidol. 2018;12:810–21 e1.

    Google Scholar 

  135. Chyzhyk V, Brown AS. Familial chylomicronemia syndrome: a rare but devastating autosomal recessive disorder characterized by refractory hypertriglyceridemia and recurrent pancreatitis. Trends Cardiovasc Med. 2020;30:80–5.

    Article  PubMed  Google Scholar 

  136. Brown WV, Goldberg I, Duell B, Gaudet D. Roundtable discussion: Familial chylomicronemia syndrome: Diagnosis and management. J Clin Lipidol. 2018;12:254–63.

    Google Scholar 

  137. Davidson M, Stevenson M, Hsieh A, Ahmad Z, Crowson C, Witztum JL. The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study. Expert Rev Cardiovasc Ther. 2017;15:415–23.

    Article  CAS  PubMed  Google Scholar 

  138. Brahm AJ, Hegele RA. Chylomicronaemia--current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11:352–62.

    Article  CAS  PubMed  Google Scholar 

  139. Beaumont JL, Carlson LA, Cooper GR, Fejfar Z, Fredrickson DS, Strasser T. Classification of hyperlipidaemias and hyperlipoproteinaemias. Bull World Health Organ. 1970;43:891–915.

    CAS  PubMed  Google Scholar 

  140. Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, Boren J, Bruckert E, Catapano AL, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655–66.

    Article  CAS  PubMed  Google Scholar 

  141. Gotoda T, Shirai K, Ohta T, Kobayashi J, Yokoyama S, Oikawa S, Bujo H, Ishibashi S, Arai H, et al. Diagnosis and management of type I and type V hyperlipoproteinemia. J Atheroscler Thromb. 2012;19:1–12.

    Article  CAS  PubMed  Google Scholar 

  142. Brahm AJ, Hegele RA. Lomitapide for the treatment of hypertriglyceridemia. Expert Opin Investig Drugs. 2016;25:1457–63.

    Article  CAS  PubMed  Google Scholar 

  143. Rabacchi C, Pisciotta L, Cefalu AB, Noto D, Fresa R, Tarugi P, Averna M, Bertolini S, Calandra S. Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. Atherosclerosis. 2015;241:79–86.

    Article  CAS  PubMed  Google Scholar 

  144. Chait A, Brunzell JD. Chylomicronemia syndrome. Adv Intern Med. 1992;37:249–73.

    CAS  PubMed  Google Scholar 

  145. Stroes E, Moulin P, Parhofer KG, Rebours V, Lohr JM, Averna M. Diagnostic algorithm for familial chylomicronemia syndrome. Atheroscler Suppl. 2017;23:1–7.

    Article  PubMed  Google Scholar 

  146. Akesson LS, Burnett JR, Mehta DK, Martin AC. Lipoprotein lipase deficiency presenting with neonatal perianal abscesses. BMJ Case Rep. 2016;29:2016.

    Google Scholar 

  147. Valdivielso P, Ramirez-Bueno A, Ewald N. Current knowledge of hypertriglyceridemic pancreatitis. Eur J Intern Med. 2014;25:689–94.

    Article  CAS  PubMed  Google Scholar 

  148. Wang Z, Li S, Sun L, Fan J, Liu Z. Comparative analyses of lipoprotein lipase, hepatic lipase, and endothelial lipase, and their binding properties with known inhibitors. PLoS One. 2013;8:e72146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Young SG, Zechner R. Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes Dev. 2013;27:459–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Hu X, Dallinga-Thie GM, Hovingh GK, Chang SY, Sandoval NP, Dang TLP, Fukamachi I, Miyashita K, Nakajima K, et al. GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia. J Clin Lipidol. 2017;11:964–71.

    Google Scholar 

  151. Beigneux AP, Miyashita K, Ploug M, Blom DJ, Ai M, Linton MF, Khovidhunkit W, Dufour R, Garg A, et al. Autoantibodies against GPIHBP1 as a cause of hypertriglyceridemia. N Engl J Med. 2017;376:1647–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Sakurai T, Sakurai A, Vaisman BL, Amar MJ, Liu C, Gordon SM, Drake SK, Pryor M, Sampson ML, et al. Creation of Apolipoprotein C-II (ApoC-II) mutant mice and correction of their hypertriglyceridemia with an ApoC-II mimetic peptide. J Pharmacol Exp Ther. 2016;356:341–53.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Ueda M, Dunbar RL, Wolska A, Sikora TU, Escobar MDR, Seliktar N. deGoma E, DerOhannessian S, Morrell L, et al. a novel APOC2 missense mutation causing Apolipoprotein C-II deficiency with severe Triglyceridemia and pancreatitis. J Clin Endocrinol Metab. 2017;102:1454–7.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Charlton-Menys V, Durrington PN. Apolipoprotein A5 and hypertriglyceridemia. Clin Chem. 2005;51:295–7.

    Article  CAS  PubMed  Google Scholar 

  155. Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, Geary RS, Hughes SG, Viney NJ, et al. Antisense inhibition of Apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438–47.

    Article  CAS  PubMed  Google Scholar 

  156. Gaudet D. Novel therapies for severe dyslipidemia originating from human genetics. Curr Opin Lipidol. 2016;27:112–24.

    Article  CAS  PubMed  Google Scholar 

  157. Gaudet D, Stroes ES, Methot J, Brisson D, Tremblay K, Bernelot Moens SJ, Iotti G, Rastelletti I, Ardigo D, et al. Long-term retrospective analysis of gene therapy with alipogene tiparvovec and its effect on lipoprotein lipase deficiency-induced pancreatitis. Hum Gene Ther. 2016;27:916–25.

    Article  CAS  PubMed  Google Scholar 

  158. Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–6.

    Article  PubMed  CAS  Google Scholar 

  159. Contreras-Bolivar V, Gonzalez-Molero I, Valdivieso P, Olveira G. Total parenteral nutrition in a pregnant patient with acute pancreatitis and lipoprotein lipase deficiency. Nutr Hosp. 2015;32:1837–40.

    PubMed  Google Scholar 

  160. Sivakumaran P, Tabak SW, Gregory K, Pepkowitz SH, Klapper EB. Management of familial hypertriglyceridemia during pregnancy with plasma exchange. J Clin Apher. 2009;24:42–6.

    Article  PubMed  Google Scholar 

  161. Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk reduction. Cardiovasc Diabetol. 2012;11:125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rocha NA, East C, Zhang J, McCullough PA. ApoCIII as a cardiovascular risk factor and modulation by the novel lipid-lowering agent Volanesorsen. Curr Atheroscler Rep. 2017;19:62.

    Article  PubMed  CAS  Google Scholar 

  163. Panta R, Dahal K, Kunwar S. Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials. J Clin Lipidol. 2015;9:217–25.

    Article  PubMed  Google Scholar 

  164. Gryn SE, Hegele RA. New oral agents for treating dyslipidemia. Curr Opin Lipidol. 2016;27:579–84.

    Article  CAS  PubMed  Google Scholar 

  165. Gaudet D, Bernelot-Moens S, Zhou Y, Keefe D, Wright M, Patel S, ESG S. Pradigastat, a diacylglycerol acyltransferase 1 inhibitor, reduces fasting triglyceride levels in familial chylomicronemia. J Clin Lipidol. 2015;9:449–50.

    Article  Google Scholar 

  166. Falko JM. Familial Chylomicronemia syndrome: a clinical guide for endocrinologists. Endocr Pract. 2018;24:756–63.

    Article  PubMed  Google Scholar 

  167. Gaudet D, Gipe DA, Pordy R, Ahmad Z, Cuchel M, Shah PK, Chyu KY, Sasiela WJ, Chan KC, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med. 2017;377:296–7.

    Article  PubMed  Google Scholar 

  168. U.S. National Library of Medicine. Familial HDL deficiency. Genetics Home Reference 2020 cited 2020; Available from: https://ghr.nlm.nih.gov/condition/familial-hdl-deficiency.

  169. Geller AS, Polisecki EY, Diffenderfer MR, Asztalos BF, Karathanasis SK, Hegele RA, Schaefer EJ. Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. J Lipid Res. 2018;59:2421–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Schaefer EJ, Anthanont P, Diffenderfer MR, Polisecki E, Asztalos BF. Diagnosis and treatment of high density lipoprotein deficiency. Prog Cardiovasc Dis. 2016;59:97–106.

    Google Scholar 

  171. Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier disease: epidemiology, pathophysiology, and management. Am J Cardiovasc Drugs. 2012;12:303–11.

    Article  CAS  PubMed  Google Scholar 

  172. Santos RD, Asztalos BF, Martinez LR, Miname MH, Polisecki E, Schaefer EJ. Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. J Clin Lipidol. 2008;2:237–47.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Schaefer EJ, Santos RD, Asztalos BF. Marked HDL deficiency and premature coronary heart disease. Curr Opin Lipidol. 2010;21:289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Ono T, Iwasaki T, Mitaya K. Bilateral corneal opacity of fish-eye disease. JMA J. 2020;3:73–4.

    PubMed  Google Scholar 

  175. Dimick SM, Sallee B, Asztalos BF, Pritchard PH, Frohlich J, Schaefer EJ. A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy. J Clin Lipidol. 2014;8:223–30.

    Article  PubMed  Google Scholar 

  176. Sirtori CR, Calabresi L, Franceschini G, Baldassarre D, Amato M, Johansson J, Salvetti M, Monteduro C, Zulli R, et al. Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. Circulation. 2001;103:1949–54.

    Article  CAS  PubMed  Google Scholar 

  177. Shah PK, Nilsson J, Kaul S, Fishbein MC, Ageland H, Hamsten A, Johansson J, Karpe F, Cercek B. Effects of recombinant apolipoprotein A-I(Milano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 1998;97:780–5.

    Article  CAS  PubMed  Google Scholar 

  178. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292–300.

    Article  CAS  PubMed  Google Scholar 

  179. Chyu KY, Shah PK. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis. Front Pharmacol. 2015;6:187.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Hooper AJ, van Bockxmeer FM, Burnett JR. Monogenic hypocholesterolaemic lipid disorders and apolipoprotein B metabolism. Crit Rev Clin Lab Sci. 2005;42:515–45.

    Article  CAS  PubMed  Google Scholar 

  181. Bassen FA, Kornzweig AL. Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood. 1950;5:381–7.

    Article  CAS  PubMed  Google Scholar 

  182. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37:333–9.

    Article  CAS  PubMed  Google Scholar 

  183. Burnett JR, Bell DA, Hooper AJ, Hegele RA. Clinical utility gene card for: abetalipoproteinaemia. Eur J Hum Genet. 2012;20.

    Google Scholar 

  184. Di Filippo M, Crehalet H, Samson-Bouma ME, Bonnet V, Aggerbeck LP, Rabes JP, Gottrand F, Luc G, Bozon D, Sassolas A. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. J Lipid Res. 2012;53:548–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, Schmitz J, Gay G, Rader DJ, Gregg RE. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science. 1992;258:999–1001.

    Article  CAS  PubMed  Google Scholar 

  186. Sharp D, Blinderman L, Combs KA, Kienzle B, Ricci B, Wager-Smith K, Gil CM, Turck CW, Bouma ME, et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature. 1993;365:65–9.

    Article  CAS  PubMed  Google Scholar 

  187. Hooper AJ, Burnett JR. Update on primary hypobetalipoproteinemia. Curr Atheroscler Rep. 2014;16:423.

    Article  PubMed  CAS  Google Scholar 

  188. Burnett JR, Bell DA, Hooper AJ, Hegele RA. Clinical utility gene card for: familial Hypobetalipoproteinaemia (APOB). Eur J Hum Genet. 2012;20.

    Google Scholar 

  189. Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, Peretti N, Dumortier J, Zoulim F, et al. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia. J Hepatol. 2014;61:891–902.

    Article  PubMed  CAS  Google Scholar 

  190. Glueck CJ, Gartside P, Fallat RW, Sielski J, Steiner PM. Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med. 1976;88:941–57.

    CAS  PubMed  Google Scholar 

  191. Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:161–5.

    Article  CAS  PubMed  Google Scholar 

  192. Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S, Rudling M, Myrdal U, Annesi G, et al. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet. 2003;34:29–31.

    Article  CAS  PubMed  Google Scholar 

  193. Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J, Pugnet-Chardon L, Moulin P, Labarge S, et al. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis. 2010;5:24.

    Article  PubMed  PubMed Central  Google Scholar 

  194. O'Connor A. A heart risk factor even doctors know little about. New York: The New York Times; 2018.

    Google Scholar 

  195. Kronenberg F. Human genetics and the causal role of lipoprotein(a) for various diseases. Cardiovasc Drugs Ther. 2016;30:87–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Schmidt K, Noureen A, Kronenberg F, Utermann G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016;57:1339–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995;41:246–55.

    Article  CAS  PubMed  Google Scholar 

  198. Bergmark C, Dewan A, Orsoni A, Merki E, Miller ER, Shin MJ, Binder CJ, Horkko S, Krauss RM, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res. 2008;49:2230–9.

    Article  CAS  PubMed  Google Scholar 

  199. Steyrer E, Durovic S, Frank S, Giessauf W, Burger A, Dieplinger H, Zechner R, Kostner GM. The role of lecithin: cholesterol acyltransferase for lipoprotein (a) assembly. Structural integrity of low density lipoproteins is a prerequisite for Lp(a) formation in human plasma. J Clin Invest. 1994;94:2330–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Kraft HG, Lingenhel A, Kochl S, Hoppichler F, Kronenberg F, Abe A, Muhlberger V, Schonitzer D, Utermann G. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. Arterioscler Thromb Vasc Biol. 1996;16:713–9.

    Article  CAS  PubMed  Google Scholar 

  201. Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, Francis GA, Genest J Jr, Grover S, et al. 2016 Canadian cardiovascular society guidelines for the Management of Dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2016;32:1263–82.

    Article  PubMed  Google Scholar 

  202. Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol. 2016;36:2239–45.

    Article  CAS  PubMed  Google Scholar 

  203. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273:6–30.

    Article  CAS  PubMed  Google Scholar 

  204. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–28.

    Article  CAS  PubMed  Google Scholar 

  205. Marcovina SM, Albers JJ, Wijsman E, Zhang Z, Chapman NH, Kennedy H. Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans. J Lipid Res. 1996;37:2569–85.

    Article  CAS  PubMed  Google Scholar 

  206. Sandholzer C, Saha N, Kark JD, Rees A, Jaross W, Dieplinger H, Hoppichler F, Boerwinkle E, Utermann G. Apo(a) isoforms predict risk for coronary heart disease. A study in six populations. Arterioscler Thromb. 1992;12:1214–26.

    Article  CAS  PubMed  Google Scholar 

  207. Mooser V, Scheer D, Marcovina SM, Wang J, Guerra R, Cohen J, Hobbs HH. The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am J Hum Genet. 1997;61:402–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Virani SS, Brautbar A, Davis BC, Nambi V, Hoogeveen RC, Sharrett AR, Coresh J, Mosley TH, Morrisett JD, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the atherosclerosis risk in communities (ARIC) study. Circulation. 2012;125:241–9.

    Article  CAS  PubMed  Google Scholar 

  209. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–52.

    Google Scholar 

  210. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Genest JJ Jr, Martin-Munley SS, McNamara JR, Ordovas JM, Jenner J, Myers RH, Silberman SR, Wilson PW, Salem DN, Schaefer EJ. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992;85:2025–33.

    Article  PubMed  Google Scholar 

  212. Marcovina SM, Koschinsky ML, Albers JJ, Skarlatos S. Report of the National Heart, Lung, and Blood Institute workshop on lipoprotein(a) and cardiovascular disease: recent advances and future directions. Clin Chem. 2003;49:1785–96.

    Article  CAS  PubMed  Google Scholar 

  213. Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg K, Couderc R, Dati F, Rifai N, 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;46:1956–67.

    Article  CAS  PubMed  Google Scholar 

  214. Bennet A, Di Angelantonio E, Erqou S, Eiriksdottir G, Sigurdsson G, Woodward M, Rumley A, Lowe GD, Danesh J, Gudnason V. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med. 2008;168:598–608.

    Article  CAS  PubMed  Google Scholar 

  215. Emerging Risk Factors C, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–23.

    Google Scholar 

  216. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018;392:1311–20.

    Article  CAS  PubMed  Google Scholar 

  217. Stubbs P, Seed M, Lane D, Collinson P, Kendall F, Noble M. Lipoprotein(a) as a risk predictor for cardiac mortality in patients with acute coronary syndromes. Eur Heart J. 1998;19:1355–64.

    Article  CAS  PubMed  Google Scholar 

  218. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–9.

    Article  CAS  PubMed  Google Scholar 

  219. Sofi F, Marcucci R, Abbate R, Gensini GF, Prisco D. Lipoprotein (a) and venous thromboembolism in adults: a meta-analysis. Am J Med. 2007;120:728–33.

    Article  CAS  PubMed  Google Scholar 

  220. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2014;63:470–7.

    Article  CAS  PubMed  Google Scholar 

  221. Capoulade R, Chan KL, Yeang C, Mathieu P, Bosse Y, Dumesnil JG, Tam JW, Teo KK, Mahmut A, et al. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol. 2015;66:1236–46.

    Article  CAS  PubMed  Google Scholar 

  222. Chan KL, Teo K, Dumesnil JG, Ni A, Tam J, Investigators A. Effect of lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation. 2010;121:306–14.

    Article  CAS  PubMed  Google Scholar 

  223. Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV, Peloso GM, Kerr KF, Pechlivanis S, Budoff MJ, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, Saleheen D, Kyriakou T, Nelson CP, et al. A comprehensive 1,000 genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet. 2015;47:1121–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Gambhir JK, Kaur H, Prabhu KM, Morrisett JD, Gambhir DS. Association between lipoprotein(a) levels, apo(a) isoforms and family history of premature CAD in young Asian Indians. Clin Biochem. 2008;41:453–8.

    Article  CAS  PubMed  Google Scholar 

  226. Cai DP, He YM, Yang XJ, Zhao X, Xu HF. Lipoprotein (a) is a risk factor for coronary artery disease in Chinese Han ethnic population modified by some traditional risk factors: a cross-sectional study of 3462 cases and 6125 controls. Clin Chim Acta. 2015;451:278–86.

    Article  CAS  PubMed  Google Scholar 

  227. Lanktree MB, Anand SS, Yusuf S, Hegele RA, Investigators S. Comprehensive analysis of genomic variation in the LPA locus and its relationship to plasma lipoprotein(a) in south Asians, Chinese, and European Caucasians. Circ Cardiovasc Genet. 2010;3:39–46.

    Article  CAS  PubMed  Google Scholar 

  228. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69:692–711.

    Article  CAS  PubMed  Google Scholar 

  229. Nordestgaard BG, Langsted A. How does elevated lipoprotein(a) cause aortic valve stenosis? J Am Coll Cardiol. 2015;66:1247–9.

    Article  PubMed  Google Scholar 

  230. Smolders B, Lemmens R, Thijs V. Lipoprotein (a) and stroke: a meta-analysis of observational studies. Stroke. 2007;38:1959–66.

    Article  CAS  PubMed  Google Scholar 

  231. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, Marcovina S, Danesh J. Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol. 2010;55:2160–7.

    Article  CAS  PubMed  Google Scholar 

  232. Sechi LA, Kronenberg F, De Carli S, Falleti E, Zingaro L, Catena C, Utermann G, Bartoli E. Association of serum lipoprotein(a) levels and apolipoprotein(a) size polymorphism with target-organ damage in arterial hypertension. JAMA. 1997;277:1689–95.

    Article  CAS  PubMed  Google Scholar 

  233. Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res. 2016;57:745–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer M, Kronenberg F, Wiedermann CJ, Oberthaler S, Xu Q, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007;27:1788–95.

    Article  CAS  PubMed  Google Scholar 

  235. van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, et al. Oxidized phospholipids on lipoprotein(a) elicit Arterial Wall inflammation and an inflammatory monocyte response in humans. Circulation. 2016;134:611–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Paige E, Masconi KL, Tsimikas S, Kronenberg F, Santer P, Weger S, Willeit J, Kiechl S, Willeit P. Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature. Cardiovasc Diabetol. 2017;16:38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Spence JD, Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity: prothrombotic, proatherosclerotic, or both? Arterioscler Thromb Vasc Biol. 2012;32:1550–1.

    Article  CAS  PubMed  Google Scholar 

  238. Leibundgut G, Scipione C, Yin H, Schneider M, Boffa MB, Green S, Yang X, Dennis E, Witztum JL, et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res. 2013;54:2815–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Tsimikas S, Mallat Z, Talmud PJ, Kastelein JJ, Wareham NJ, Sandhu MS, Miller ER, Benessiano J, Tedgui A, et al. Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol. 2010;56:946–55.

    Article  CAS  PubMed  Google Scholar 

  240. Tsimikas S, Willeit P, Willeit J, Santer P, Mayr M, Xu Q, Mayr A, Witztum JL, Kiechl S. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol. 2012;60:2218–29.

    Article  CAS  PubMed  Google Scholar 

  241. Bertoia ML, Pai JK, Lee JH, Taleb A, Joosten MM, Mittleman MA, Yang X, Witztum JL, Rimm EB, et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J Am Coll Cardiol. 2013;61:2169–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Tsimikas S, Duff GW, Berger PB, Rogus J, Huttner K, Clopton P, Brilakis E, Kornman KS, Witztum JL. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol. 2014;63:1724–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Byun YS, Lee JH, Arsenault BJ, Yang X, Bao W, DeMicco D, Laskey R, Witztum JL, Tsimikas S, Investigators TNTT. Relationship of oxidized phospholipids on apolipoprotein B-100 to cardiovascular outcomes in patients treated with intensive versus moderate atorvastatin therapy: the TNT trial. J Am Coll Cardiol. 2015;65:1286–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Nsaibia MJ, Mahmut A, Boulanger MC, Arsenault BJ, Bouchareb R, Simard S, Witztum JL, Clavel MA, Pibarot P, et al. Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease. J Intern Med. 2016;280:509–17.

    Article  CAS  PubMed  Google Scholar 

  245. Scipione CA, Sayegh SE, Romagnuolo R, Tsimikas S, Marcovina SM, Boffa MB, Koschinsky ML. Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a). J Lipid Res. 2015;56:2273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Wiesner P, Tafelmeier M, Chittka D, Choi SH, Zhang L, Byun YS, Almazan F, Yang X, Iqbal N, et al. MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma. J Lipid Res. 2013;54:1877–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. van Dijk RA, Kolodgie F, Ravandi A, Leibundgut G, Hu PP, Prasad A, Mahmud E, Dennis E, Curtiss LK, et al. Differential expression of oxidation-specific epitopes and apolipoprotein(a) in progressing and ruptured human coronary and carotid atherosclerotic lesions. J Lipid Res. 2012;53:2773–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  248. Ravandi A, Leibundgut G, Hung MY, Patel M, Hutchins PM, Murphy RC, Prasad A, Mahmud E, Miller YI, et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans. J Am Coll Cardiol. 2014;63:1961–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Yeang C, Wilkinson MJ, Tsimikas S. Lipoprotein(a) and oxidized phospholipids in calcific aortic valve stenosis. Curr Opin Cardiol. 2016;31:440–50.

    Article  PubMed  PubMed Central  Google Scholar 

  250. Kyriakou T, Seedorf U, Goel A, Hopewell JC, Clarke R, Watkins H, Farrall M, Consortium P. A common LPA null allele associates with lower lipoprotein(a) levels and coronary artery disease risk. Arterioscler Thromb Vasc Biol. 2014;34:2095–9.

    Article  CAS  PubMed  Google Scholar 

  251. Lim ET, Wurtz P, Havulinna AS, Palta P, Tukiainen T, Rehnstrom K, Esko T, Magi R, Inouye M, et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 2014;10:e1004494.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  252. Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, Xu Q, Mayr A, Willeit J, Tsimikas S. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck study. J Am Coll Cardiol. 2014;64:851–60.

    Article  PubMed  Google Scholar 

  253. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J, Ridker PM, Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating Rosuvastatin). Circulation. 2014;129:635–42.

    Article  CAS  PubMed  Google Scholar 

  254. Albers JJ, Slee A, O'Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, Xu P, Marcovina SM. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis intervention in metabolic syndrome with Low HDL/high triglyceride and impact on Global Health outcomes). J Am Coll Cardiol. 2013;62:1575–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown AS, Brown WV, Cromwell WC, Goldberg RB, et al. Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol. 2011;5:338–67.

    Article  PubMed  Google Scholar 

  256. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61:1146–56.

    Article  CAS  PubMed  Google Scholar 

  257. van Capelleveen JC, van der Valk FM, Stroes ES. Current therapies for lowering lipoprotein (a). J Lipid Res. 2016;57:1612–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  258. Maher VM, Brown BG. Lipoprotein (a) and coronary heart disease. Curr Opin Lipidol. 1995;6:229–35.

    Article  CAS  PubMed  Google Scholar 

  259. Thompson GR, Maher VM, Matthews S, Kitano Y, Neuwirth C, Shortt MB, Davies G, Rees A, Mir A, et al. Familial Hypercholesterolaemia regression study: a randomised trial of low-density-lipoprotein apheresis. Lancet. 1995;345:811–6.

    Article  CAS  PubMed  Google Scholar 

  260. Bouchareb R, Mahmut A, Nsaibia MJ, Boulanger MC, Dahou A, Lepine JL, Laflamme MH, Hadji F, Couture C, et al. Autotaxin derived from lipoprotein(a) and valve interstitial cells promotes inflammation and mineralization of the aortic valve. Circulation. 2015;132:677–90.

    Article  CAS  PubMed  Google Scholar 

  261. Shlipak MG, Simon JA, Vittinghoff E, Lin F, Barrett-Connor E, Knopp RH, Levy RI, Hulley SB. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000;283:1845–52.

    Article  CAS  PubMed  Google Scholar 

  262. Stuenkel CA, Davis SR, Gompel A, Lumsden MA, Murad MH, Pinkerton JV, Santen RJ. Treatment of symptoms of the menopause: an Endocrine Society clinical practice Guideline. J Clin Endocrinol Metab. 2015;100:3975–4011.

    Article  CAS  PubMed  Google Scholar 

  263. Hossne NA, Cruz E, Buffolo E, Coimbra AC, Machado J, Goldenberg RC, Regazzi G, Azevedo S, Invitti AL, et al. Long-term and sustained therapeutic results of a specific Promonocyte cell formulation in refractory angina: ReACT((R)) (refractory angina cell therapy) clinical update and cost-effective analysis. Cell Transplant. 2015;24:955–70.

    Article  PubMed  Google Scholar 

  264. Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H, Blom D, Eriksson M, Dent R, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278–88.

    Article  CAS  PubMed  Google Scholar 

  265. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, Langslet G, Scott R, Olsson AG, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331–40.

    Article  CAS  PubMed  Google Scholar 

  266. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, et al. Effects of Proprotein convertase Subtilisin/Kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:40–51.

    Article  PubMed  Google Scholar 

  267. O'Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019;139:1483–92.

    Article  CAS  PubMed  Google Scholar 

  268. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, Parhofer K, Ramlow W, Koch M, et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med. 2009;6:229–39.

    CAS  PubMed  Google Scholar 

  269. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, Maerz W, Lehmacher W, et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation. 2013;128:2567–76.

    Article  CAS  PubMed  Google Scholar 

  270. Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CM, Catanese JJ, Buring JE, Devlin JJ, Ridker PM. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. 2009;203:371–6.

    Article  CAS  PubMed  Google Scholar 

  271. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu RZ, Marcovina SM, Hughes SG, Graham MJ, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388:2239–53.

    Article  CAS  PubMed  Google Scholar 

  272. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF, Burkey JL, Yang Q, Marcovina SM, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386:1472–83.

    Article  CAS  PubMed  Google Scholar 

  273. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, Schmidt K, Zhao C, Aghajan M, et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res. 2014;42:8796–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Late-Breaking Science Abstracts From the American Heart Association's Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018. Circulation. 2018;138:e751–82.

    Google Scholar 

  275. Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, Willeit P, Young R, Surendran P, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3:619–27.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgement

To Sheba Khan for assistance on the Lp(a) section.

Author information

Authors and Affiliations

  1. Division of Cardiology and Lipid Clinic, Advocate Lutheran General Hospital, Park Ridge, IL, USA

    Alan S. Brown

  2. Division of Cardiology, Advocate Lutheran General Hospital, Park Ridge, IL, USA

    Ehab G. Dababneh & Adib Chaus

  3. Prairie Cardiovascular Consultants, Southern Illinois Healthcare, Department of Cardiology, Clinical Associate Professor, Southern Illinois University, Carbondale, IL, USA

    Vadzim Chyzhyk

  4. Prairie Cardiovascular Consultants, Southern Illinois Healthcare, Carbondale, IL, USA

    Vadzim Chyzhyk

  5. Department of Cardiology, Advocate Medical Group at Advocate Aurora Health, Naperville, IL, USA

    Victor Marinescu

  6. Division of Cardiology, Cook County Health, Chicago, IL, USA

    Nataliya Pyslar

  7. Department of Medicine, RUSH Medical College, Chicago, IL, USA

    Nataliya Pyslar

Authors
  1. Alan S. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ehab G. Dababneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adib Chaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vadzim Chyzhyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Victor Marinescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nataliya Pyslar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan S. Brown .

Editor information

Editors and Affiliations

  1. The University of Chicago Pritzker School of Medicine, Chicago, IL, USA

    Michael H. Davidson

  2. Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Univerity School of Medicine, Baltimore, MD, USA

    Peter P. Toth

  3. Department of Applied Health Science, Indiana University School of Public Health, Bloomington, IN, USA

    Kevin C. Maki

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Brown, A.S., Dababneh, E.G., Chaus, A., Chyzhyk, V., Marinescu, V., Pyslar, N. (2021). Genetic Disorders of Lipoprotein Metabolism. In: Davidson, M.H., Toth, P.P., Maki, K.C. (eds) Therapeutic Lipidology. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-030-56514-5_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-56514-5_3

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-56513-8

  • Online ISBN: 978-3-030-56514-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation