Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment with Alirocumab, a PCSK9 Monoclonal Antibody

Circulation: Cardiovascular Genetics

Volumn 8, Issue 6, 2015, Pages 823-831

  Hopkins, Paul N ^a   Defesche, Joep ^a   Fouchier, Sigrid W ^a   Bruckert, Eric ^a   Luc, Gerald ^a   Cariou, Bertrand ^a   Sjouke, Barbara ^a   Leren, Trond P ^a   Harada Shiba, Mariko ^a   Mabuchi, Hiroshi ^a   Rabès, Jean Pierre ^a   Carrie, Alain ^a   Van Heyningen, Charles ^a   Carreau, Valerie ^a   Farnier, Michel ^a   Teoh, Yee P ^a   Bourbon, Mafalda ^a   Kawashiri, Masa Aki ^a   Nohara, Atsushi ^a   Soran, Handrean ^a   Marais, A David ^a   Tada, Hayato ^a   Abifadel, Marianne ^a   Boileau, Catherine ^a   Chanu, Bernard ^a   Katsuda, Shoji ^a   Kishimoto, Ichiro ^a   Lambert, Gilles ^a   Makino, Hisashi ^a   Miyamoto, Yoshihiro ^a   Pichelin, Matthieu ^a   Yagi, Kunimasa ^a   Yamagishi, Masakazu ^a   Zair, Yassine ^a   Mellis, Scott ^a   Yancopoulos, George D ^a   Stahl, Neil ^a   Mendoza, Johanna ^a   Du, Yunling ^a   Hamon, Sara ^a   Krempf, Michel ^a   Swergold, Gary D ^a   more..

^a UNIVERSITY OF UTAH   (United States)

Author keywords

Alirocumab; cardiovascular diseases; clinical trial; genetics; human; hypercholesterolemia; PCSK9 protein

Indexed keywords

ALIROCUMAB; APOLIPOPROTEIN B; CREATINE KINASE; GLUCOSE; LIVER ENZYME; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; SERINE PROTEINASE; UNCLASSIFIED DRUG; MONOCLONAL ANTIBODY; PCSK9 PROTEIN, HUMAN;

ADULT; AGED; ARTICLE; AUTOSOMAL DOMINANT DISORDER; AUTOSOMAL DOMINANT HYPERCHOLESTEROLEMIA; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; CORONARY ARTERY DISEASE; CREATINE KINASE BLOOD LEVEL; CROSS-SECTIONAL STUDY; DOUBLE BLIND PROCEDURE; FEMALE; GAIN OF FUNCTION MUTATION; GASTROENTERITIS; GLUCOSE BLOOD LEVEL; HETEROZYGOTE; HUMAN; HYPERCHOLESTEROLEMIA; INFECTION; INTERVENTION STUDY; LOWER RESPIRATORY TRACT INFECTION; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; OBSERVATIONAL STUDY; PATHOGENESIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RETROSPECTIVE STUDY; SIDE EFFECT; THORAX PAIN; TREATMENT DURATION; TREATMENT OUTCOME; UNSPECIFIED SIDE EFFECT; UPPER RESPIRATORY TRACT INFECTION; ADOLESCENT; ANTAGONISTS AND INHIBITORS; BLOOD; CLINICAL TRIAL; COMPARATIVE STUDY; GENETICS; HYPERLIPOPROTEINEMIA TYPE II; METABOLISM; MIDDLE AGED; MUTATION;

ADOLESCENT; ADULT; AGED; ANTIBODIES, MONOCLONAL; CHOLESTEROL, LDL; CORONARY ARTERY DISEASE; DOUBLE-BLIND METHOD; FEMALE; HUMANS; HYPERLIPOPROTEINEMIA TYPE II; MALE; MIDDLE AGED; MUTATION; PROPROTEIN CONVERTASES; SERINE ENDOPEPTIDASES;

EID: 84948580064     PISSN: 1942325X     EISSN: 19423268     Source Type: Journal    
DOI: 10.1161/CIRCGENETICS.115.001129     Document Type: Article

References (28)

1. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, et al.; European Atherosclerosis Society Consensus Panel. 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;34:3478-3490. doi: 10.1093/eurheartj/eht273.
2. Sjouke B, Kusters DM, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2015;36:560-565. doi: 10.1093/eurheartj/ehu058.
3. Varret M, Rabès JP, Saint-Jore B, Cenarro A, Marinoni JC, Civeira F, et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am J Hum Genet. 1999;64:1378-1387. doi: 10.1086/302370.
4. Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, Wardell BB, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol. 2000;20:1089-1093.
5. Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-156. doi: 10.1038/ng1161.
6. Timms KM, Wagner S, Samuels ME, Forbey K, Goldfine H, Jammulapati S, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet. 2004;114:349-353. doi: 10.1007/s00439-003-1071-9.
7. Leren TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65:419-422. doi: 10.1111/j.0009-9163.2004.0238.x
8. Sun XM, Eden ER, Tosi I, Neuwirth CK, Wile D, Naoumova RP, et al. Evidence for effect of mutant PCSK9 on apolipoprotein B secretion as the cause of unusually severe dominant hypercholesterolaemia. Hum Mol Genet. 2005;14:1161-1169. doi: 10.1093/hmg/ddi128.
9. Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, et al. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat. 2005;26:497. doi: 10.1002/humu.9383.
10. Homer VM, Marais AD, Charlton F, Laurie AD, Hurndell N, Scott R, et al. Identification and characterization of two non-secreted PCSK9 mutants associated with familial hypercholesterolemia in cohorts from New Zealand and South Africa. Atherosclerosis. 2008;196:659-666. doi: 10.1016/j.atherosclerosis.2007.07.022.
11. Miyake Y, Kimura R, Kokubo Y, Okayama A, Tomoike H, Yamamura T, et al. Genetic variants in PCSK9 in the Japanese population: rare genetic variants in PCSK9 might collectively contribute to plasma LDL cholesterol levels in the general population. Atherosclerosis. 2008;196:29-36. doi: 10.1016/j.atherosclerosis.2006.12.035.
12. Noguchi T, Katsuda S, Kawashiri MA, Tada H, Nohara A, Inazu A, et al. The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation. Atherosclerosis. 2010;210:166-172. doi: 10.1016/j.atherosclerosis.2009.11.018.
13. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009;50:S172-S177. doi: 10.1194/jlr. R800091-JLR200.
14. Lo Surdo P, Bottomley MJ, Calzetta A, Settembre EC, Cirillo A, Pandit S, et al. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH. EMBO Rep. 2011;12:1300-1305. doi: 10.1038/embor.2011.205.
15. Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53:2515-2524. doi: 10.1194/jlr.R026658.
16. Wang Y, Huang Y, Hobbs HH, Cohen JC. Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res. 2012;53:1932-1943. doi: 10.1194/jlr.M028563.
17. Seidah NG, Awan Z, Chrétien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114:1022-1036. doi: 10.1161/CIRCRESAHA.114.301621.
18. Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA. 2004;101:7100-7105. doi: 10.1073/pnas.0402133101.
19. Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108-1118. doi: 10.1056/NEJMoa1105803.
20. Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380:29-36. doi: 10.1016/S0140-6736(12)60771-5.
21. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, et al.; LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, doseranging, phase 2 study. Lancet. 2012;380:2007-2017. doi: 10.1016/S0140-6736(12)61770-X
22. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497-2506. doi: 10.1001/jama.2012.25790.
23. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Lowdensity lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation. 2012;126:2408-2417. doi: 10.1161/CIRCULATIONAHA.112.144055.
24. Feldman B, Wang E, Willan A, Szalai JP. The randomized placebo-phase design for clinical trials. J Clin Epidemiol. 2001;54:550-557.
25. Fouchier SW, Kastelein JJ, Defesche JC. Update of the molecular basis of familial hypercholesterolemia in the Netherlands. Hum Mutat. 2005;26:550-556. doi: 10.1002/humu.20256.
26. Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet. 2001;357:165-168. doi: 10.1016/S0140-6736(00)03587-X
27. Haddad L, Day IN, Hunt S, Williams RR, Humphries SE, Hopkins PN. Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred. J Lipid Res. 1999;40:1113-1122.
28. Leren TP. Cascade genetic screening for familial hypercholesterolemia. Clin Genet. 2004;66:483-487. doi: 10.1111/j.1399-0004.2004.00320.x.