Rare dyslipidaemias, from phenotype to genotype to management: a European Atherosclerosis Society task force consensus statement

1       Richter T, Nestler-Parr S, Babela R, et al. Rare disease terminology and definitions—a systematic global review: report of the ISPOR rare disease special interest group. Value Health 2015; 18: 906–14.

2       European Medicines Agency. Orphan designation: overview. https://www.ema.europa.eu/en/human-regulatory/overview/ orphan-designation-overview (accessed April 4, 2019).

3       Orphan Drug Act. Rare diseases act of 2002. https://www.govinfo. gov/content/pkg/PLAW-107publ280/html/PLAW-107publ280.htm (accessed April 4, 2019).

4       EURORDIS. Fact sheet. What is a rare disease? https://www. eurordis.org/sites/default/files/publications/Fact_Sheet_RD.pdf (accessed April 9, 2019).

5       Boycott KM, Hartley T, Biesecker LG, et al. A diagnosis for all rare genetic diseases: the horizon and the next frontiers. Cell 2019; 177: 32–37.

6       Dron JS, Hegele RA. Polygenic influences on dyslipidemias. Curr Opin Lipidol 2018; 29: 133–43.

7       Hegele RA, Ban MR, Cao H, McIntyre AD, Robinson JF, Wang J. Targeted next-generation sequencing in monogenic dyslipidemias. Curr Opin Lipidol 2015; 26: 103–13.

8       Hegele RA. Plasma lipoproteins: genetic influences and clinical implications. Nat Rev Genet 2009; 10: 109–21.

9       Nordestgaard BG, Chapman MJ, Humphries SE, 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.

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

11     Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014; 35: 2146–57.

12     Arca M, Zuliani G, Wilund K, et al. Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis. Lancet 2002; 359: 841–47.

13     Iacocca MA, Chora JR, Carrié A, et al. ClinVar database of global familial hypercholesterolemia-associated DNA variants. Hum Mutat 2018; 39: 1631–40.

14     Andersen LH, Miserez AR, Ahmad Z, Andersen RL. Familial defective apolipoprotein B-100: a review. J Clin Lipidol 2016; 10: 1297–302.

15     Dron JS, Hegele RA. Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants. Curr Opin Lipidol 2017; 28: 161–69.

16     Wang J, Dron JS, Ban MR, et al. Polygenic versus monogenic causes of hypercholesterolemia ascertained clinically. Arterioscler Thromb Vasc Biol 2016; 36: 2439–45.

17     Berberich AJ, Hegele RA. The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol 2019; 16: 9–20.

18     Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency—an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis 2014; 235: 21–30.

19     Julius U. Current role of lipoprotein apheresis in the treatment of high-risk patients. J Cardiovasc Dev Dis 2018; 5: e27.

20     Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol 2017; 5: 280–90.

21     Blom DJ, Averna MR, Meagher EA, et al. Long-term efficacy and safety of the microsomal triglyceride transfer protein inhibitor lomitapide in patients with homozygous familial hypercholesterolemia. Circulation 2017; 136: 332–35.

22     Hegele RA, Tsimikas S. Lipid-lowering agents. Circ Res 2019; 124: 386–404.

23     Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017; 377: 296–97.

24     Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical presentation and laboratory diagnosis. J Clin Pathol 2008; 61: 588–94.

25     Burton BK, Balwani M, Feillet F, et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. N Engl J Med 2015; 373: 1010–20.

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

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

28     Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis 2014; 37: 333–39.

29     Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol 2014; 25: 161–68.

30     Parhofer KG, Barrett PH, Bier DM, Schonfeld G. Lipoproteins containing the truncated apolipoprotein, Apo B-89, are cleared from human plasma more rapidly than Apo B-100-containing lipoproteins in vivo. J Clin Invest 1992; 89: 1931–37.

31     Welty FK, Lichtenstein AH, Barrett PH, Dolnikowski GG, Ordovas JM, Schaefer EJ. Decreased production and increased catabolism of apolipoprotein B-100 in apolipoprotein B-67/B-100 heterozygotes. Arterioscler Thromb Vasc Biol 1997; 17: 881–88.

32     Parhofer KG, Barrett PH, Aguilar-Salinas CA, Schonfeld G. Positive linear correlation between the length of truncated apolipoprotein B and its secretion rate: in vivo studies in human apoB-89, apoB-75, apoB-54.8, and apoB-31 heterozygotes. J Lipid Res 1996; 37: 844–52.

33     Levy E, Poinsot P, Spahis S. Chylomicron retention disease: genetics, biochemistry, and clinical spectrum. Curr Opin Lipidol 2019; 30: 134–39.

34     Minicocci I, Montali A, Robciuc M R, et al. Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. J Clin Endocrinol Metab 2012; 97: e1266–75.

35     Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363: 2220–27.

36     Zhao Z, Tuakli-Wosornu Y, Lagace TA, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79: 514–23.

37     Di Costanzo A, Di Leo E, Noto D, et al. Clinical and biochemical characteristics of individuals with low cholesterol syndromes: a comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia. J Clin Lipidol 2017; 11: 1234–42.

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

39     Dron JS, Wang J, Cao H, et al. Severe hypertriglyceridemia is primarily polygenic. J Clin Lipidol 2019; 13: 80–88.

40     Dron JS, Hegele RA. Genetics of triglycerides and the risk of atherosclerosis. Curr Atheroscler Rep 2017; 19: 31.

41     Hegele RA, Berberich AJ, Ban MR, et al. Clinical and biochemical features of different molecular etiologies of familial chylomicronemia. J Clin Lipidol 2018; 12: 920–27.

42     Péterfy M. Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism. Biochim Biophys Acta 2012; 1821: 790–94.

43     Fong LG, Young SG, Beigneux AP, et al. GPIHBP1 and plasma triglyceride metabolism. Trends Endocrinol Metab 2016; 27: 455–69.

44     Iacocca MA, Dron JS, Hegele RA. Progress in finding pathogenic DNA copy number variations in dyslipidemia. Curr Opin Lipidol 2019; 30: 63–70.

45     Basel-Vanagaite L, Zevit N, Har Zahav A, et al. Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1. Am J Hum Genet 2012; 90: 49–60.

46     Lee JH, Giannikopoulos P, Duncan SA, et al. The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat Med 2011; 17: 812–15.

47     Rees MG, Raimondo A, Wang J, et al. Inheritance of rare functional GCKR variants and their contribution to triglyceride levels in families. Hum Mol Genet 2014; 23: 5570–78.

48     Paquette M, Bernard S, Hegele RA, Baass A. Chylomicronemia— differences between familial chylomicronemia syndrome and multifactorial chylomicronemia. Atherosclerosis 2019; 283: 137–42.

49     Berberich AJ, Ziada A, Zou GY, Hegele RA. Conservative management in hypertriglyceridemia-associated pancreatitis. J Intern Med 2019; published online May 11. DOI:10.1111/joim.12925.

50     Goldberg AS, Hegele RA. Severe hypertriglyceridemia in pregnancy. J Clin Endocrinol Metab 2012; 97: 2589–96.

51     Alexander VJ, Xia S, Hurh E, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J 2019; published online April 24. DOI:10.1093/eurheartj/ehz209.

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

53     Sniderman AD, de Graaf J, Thanassoulis G, Tremblay AJ, Martin SS, Couture P. The spectrum of type III hyperlipoproteinemia. J Clin Lipidol 2018; 12: 1383–89.

54     Pollin T, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 2008; 322: 1702–05.

55     Langlois MR, Chapman MJ, Cobbaert C, et al. Quantifying atherogenic lipoproteins: current and future challenges in the era of personalized medicine and very low concentrations of LDL cholesterol. A consensus statement from EAS and EFLM. Clin Chem 2018; 64: 1006–33.

56     Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2016; 37: 2999–3058.

57     März W, Kleber ME, Scharnagl H, Speer T, et al. HDL cholesterol: reappraisal of its clinical relevance. Clin Res Cardiol 2017; 106: 663–75.

58     Annema W, von Eckardstein A. High-density lipoproteins. Multifunctional but vulnerable protections from atherosclerosis. Circ J 2013; 77: 2432–48.

59     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; 299: 2524–32.

60     Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–-80.

61     Bowe B, Xie Y, Xian H, Balasubramanian S, Zayed MA, Al-Aly Z. High density lipoprotein cholesterol and the risk of all-cause mortality among US veterans. Clin J Am Soc Nephrol 2016; 11: 1784–93.

62     Ko DT, Alter DA, Guo H, et al. High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART Study. J Am Coll Cardiol 2016; 68: 2073–83.

63     Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J 2017; 38: 2478–86.

64     Madsen CM, Varbo A, Tybjærg-Hansen A, Frikke-Schmidt R, Nordestgaard BG. U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. Eur Heart J 2018; 39: 1181–90.

65     Dron JS, Wang J, Low-Kam C, et al. Polygenic determinants in extremes of high-density lipoprotein cholesterol. J Lipid Res 2017; 58: 2162–70.

66     Geller AS, Polisecki EY, Diffenderfer MR, et al. Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. J Lipid Res 2018; 59: 2421–35.

67     Timmins JM, Lee JY, Boudyguina E, et al. Targeted inactivation of hepatic ABCA1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of ApoA-I. J Clin Invest 2005; 115: 1333–42.

68     Brunham LR, Kruit JK, Iqbal J, et al. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest 2006; 116: 1052–62.

69     Zhu X, Lee JY, Timmins JM, et al. Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem 2008; 283: 22930–41.

70     Rosenson RS, Brewer HB Jr, Davidson WS, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012; 125: 1905–19.

71     Fellin R, Manzato E. Lipoprotein-X fifty years after its original discovery. Nutr Metab Cardiovasc Dis 2019; 29: 4–8.

72     Calabresi L, Simonelli S, Gomaraschi M, Franceschini G. Genetic lecithin: cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis 2012; 222: 299–306.

73     Ossoli A, Neufeld EB, Thacker SG, et al. Lipoprotein X causes renal disease in LCAT deficiency. PLoS One 2016; 11: e0150083.

74     Imbasciati E, Paties C, Scarpioni L, Mihatsch MJ. Renal lesions in familial lecithin-cholesterol acyltransferase deficiency. Ultrastructural heterogeneity of glomerular changes. Am J Nephrol 1986; 6: 66–70.

75     Oldoni F, Baldassarre D, Castelnuovo S, et al. Complete and partial LCAT deficiency are differentially associated with atherosclerosis. Circulation 2018; 138: 1000–07.

76     Lu C, Zuo K, Lu Y, et al. Apolipoprotein A-1-related amyloidosis: 2 case reports and review of the literature. Medicine (Baltimore) 2017; 96: e8148.

77     Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. PLoS Genet 2012; 8: e1003063.

78     Das M, Wilson CJ, Mei X, Wales TE, Engen JR, Gursky O. Structural stability and local dynamics in disease-causing mutants of human apolipoprotein A-I: what makes the protein amyloidogenic? J Mol Biol 2016; 428: 449–62.

79     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.

80     Tanaka S, Haketa A, Sakimoto T, Abe M. A case of apolipoprotein A-I deficiency due to carboxyl-terminal truncation. J Clin Lipidol 2018; 12: 511–14.

81     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.

82     Hooper AJ, McCormick SPA, Hegele RA, Burnett JR. Clinical utility gene card for: Tangier disease. Eur J Hum Genet 2017; published online May 24. DOI:10.1038/ejhg.2017.72.

83     Muratsu J, Koseki M, Masuda D, et al. Accelerated atherogenicity in Tangier Disease. J Atheroscler Thromb 2018; 25: 1076–85.

84     Serfaty-Lacrosniere C, Civeira F, Lanzberg A, et al. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 1994; 107: 85–98.

85     Saeedi R, Li M, Frohlich J. A review on lecithin: cholesterol acyltransferase deficiency. Clin Biochem 2015; 48: 472–75.

86     Jonas A. Lecithin cholesterol acyltransferase. Biochem Biophys Acta 2000; 1529: 245–46.

87     Holleboom AG, Kuivenhoven JA, van Olden CC, et al. Proteinuria in early childhood due to familial LCAT deficiency caused by loss of a disulfide bond in lecithin:cholesterol acyl transferase. Atherosclerosis 2011; 216: 161–65.

88     Alrasadi K, Awan Z, Alwaili K, et al. Comparison of treatment of severe high-density lipoprotein cholesterol deficiency in men with daily atorvastatin (20 mg) versus fenofibrate (200 mg) versus extended-release niacin (2 g). Am J Cardiol 2008; 102: 1341–47.

89     Kootte RS, Smits LP, van der Valk FM, et al. Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA. J Lipid Res 2015; 56: 703–12.

90     Aranda P, Valdivielso P, Pisciotta L, et al. Therapeutic management of a new case of LCAT deficiency with a multifactorial long-term approach based on high doses of angiotensin II receptor blockers (ARBs). Clin Nephrol 2008; 69: 213–18.

91     Strom EH, Sund S, Reier-Nilsen M, Dorje C, Leren TP. Lecithin: cholesterol acyltransferase (LCAT) deficiency: renal lesions with early graft recurrence. Ultrastruct Pathol 2011; 35: 139–45.

92     Shamburek RD, Bakker-Arkema R, Shamburek AM, et al. Safety and tolerability of ACP-501, a recombinant human lecithin: cholesterol acyltransferase, in a phase 1 single-dose escalation study. Circ Res 2016; 118: 73–82.

93     Freeman LA, Demosky SJ Jr, Konaklieva M, et al. Lecithin: cholesterol acyltransferase activation by sulfhydryl-reactive small molecules: role of cysteine-31. J Pharmacol Exp Ther 2017; 362: 306–18.

94     Shamburek RD, Bakker-Arkema R, Auerbach BJ, et al. Familial lecithin: cholesterol acyltransferase deficiency: first-in-human treatment with enzyme replacement. J Clin Lipidol 2016; 10: 356–67.

95     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; 323: 1234–38.

96     Vergeer M, Korporaal SJ, Franssen R, et al. Genetic variant of the scavenger receptor BI in humans. N Engl J Med 2011; 364: 136–45.

97     Brunham LR, Tietjen I, Bochem AE, et al. Novel mutations in scavenger receptor BI associated with high HDL cholesterol in humans. Clin Genet 2011; 79: 575–81.

98     Zanoni P, Khetarpal SA, Larach DB, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351: 1166–71.

99     Tall AR, Rader DJ. Trials and tribulations of CETP Inhibitors.

Circ Res 2018; 122: 106–12.

100  Hegele RA, Little JA, Vezina C, et al. Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics.

Arterioscler Thromb 1995; 13: 720–08.

101  Davignon J, Dufour R. Primary hyperlipidemias. Oxford: Clinical Publishing, 2007.

102  Genest J, Hegele RA, Bergeron J, et al. Canadian Cardiovascular Society position statement on familial hypercholesterolemia. Can J Cardiol 2014; 30: 1471–81.

103  Hamel C. Retinitis pigmentosa. Orphanet J Rare Dis 2006; 1: 40.

104  Sassolas A, Filippo M Di, Aggerbeck LP, Peretti N, Samson-Bouma ME. Anderson’s disease/chylomicron retention disease and mutations in the SAR1B gene, mutations in human genetic disease. London: IntechOpen, 2012.

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

106  Ravesloot MJ, Bril H, Braamskamp MJ, Wiegman A, Wong Chung RP. The curious case of the orange coloured tonsils. Int J Ped Otorhinolaryngology 2014; 78: 2305–07.