The influence of PCSK9 polymorphisms on serum low-density lipoprotein cholesterol and risk of atherosclerosis

Current Atherosclerosis Reports

Volumn 12, Issue 5, 2010, Pages 308-315

  Davignon, Jean ^a   Dubuc, Geneviève ^a   Seidah, Nabil G ^a  

^a CLIN RESEARCH INSTITUTE OF MONTREAL   (Canada)

Author keywords

Atherosclerosis; Berberine; Cerebrovascular disease; Cholesterol homeostasis; Coronary artery disease; Fibrate; Genetic variants; LDL cholesterol; LDL receptor; Lipoprotein metabolism; Mutations; PCSK9; Peripheral arterial disease; Statin

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; ATORVASTATIN; BERBERINE; CHOLESTEROL; COMPACTIN; EZETIMIBE; FENOFIBRATE; FIBRIC ACID DERIVATIVE; FURIN; GEMFIBROZIL; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LIPOCORTIN 2; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; NEUTRALIZING ANTIBODY; PHOSPHOROTHIOIC ACID; PLACEBO; PROPROTEIN CONVERTASE SUBTILISIN KEXIN 9; PROTEIN PCSK9; SERINE PROTEINASE; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CEREBROVASCULAR DISEASE; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; DISEASE COURSE; DISEASE SEVERITY; DRUG EFFICACY; DYSLIPIDEMIA; ENZYME BLOOD LEVEL; ENZYME RELEASE; GENE MUTATION; GENE STRUCTURE; GENETIC VARIABILITY; HUMAN; HYPERCHOLESTEROLEMIA; NONHUMAN; PATHOGENESIS; PERIPHERAL VASCULAR DISEASE; PROGNOSIS; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REVIEW; RISK FACTOR; RNA INTERFERENCE; SINGLE NUCLEOTIDE POLYMORPHISM; TREATMENT RESPONSE;

ATHEROSCLEROSIS; CHOLESTEROL, LDL; DISEASE PROGRESSION; GENETIC PREDISPOSITION TO DISEASE; HUMANS; POLYMORPHISM, GENETIC; RISK FACTORS; RNA; SERINE ENDOPEPTIDASES;

EID: 77956262162     PISSN: 15233804     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11883-010-0123-6     Document Type: Review

References (50)

1. M Abifadel M Varret JP Rabes, et al. 2003 Mutations in PCSK9 cause autosomal dominant hypercholesterolemia Nat Genet 34 154 156 10.1038/ng1161 1:CAS:528:DC%2BD3sXktFSlt70%3D 12730697
2. KN Maxwell JL Breslow 2004 Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype Proc Natl Acad Sci U S A 101 7100 7105 10.1073/pnas.0402133101 1:CAS:528: DC%2BD2cXktFeqsLg%3D 15118091
3. JC Cohen E Boerwinkle TH Mosley Jr HH Hobbs 2006 Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N Engl J Med 354 1264 1272 10.1056/NEJMoa054013 1:CAS:528:DC%2BD28Xislequr8%3D 16554528
4. NG Seidah A Prat 2007 The proprotein convertases are potential targets in the treatment of dyslipidemia J Mol Med 85 685 696 10.1007/s00109-007-0172-7 1:CAS:528:DC%2BD2sXns1yntLg%3D 17351764
5. NG Seidah 2009 PCSK9 as a therapeutic target of dyslipidemia Expert opinion on therapeutic targets 13 19 28 10.1517/14728220802600715 1:CAS:528:DC%2BD1cXhsVKrtL7P 19063703
6. Davignon J, Dufour R: Primary Hyperlipidemias. Oxford: Clinical Publishing; 2007.
7. SE Leigh TP Leren SE Humphries 2009 Commentary PCSK9 variants: a new database Atherosclerosis 203 32 33 10.1016/j.atherosclerosis.2009.02.006 1:CAS:528:DC%2BD1MXis1equrY%3D 19249440
8. S Poirier G Mayer V Poupon, et al. 2009 Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route J Biol Chem 284 28856 28864 10.1074/jbc.M109.037085 1:CAS:528:DC%2BD1MXht1Cmt73O 19635789
9. A Zaid A Roubtsova R Essalmani, et al. 2008 Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration Hepatology 48 646 654 10.1002/hep.22354 1:CAS:528:DC%2BD1cXhtVCqt7nO 18666258
10. S Benjannet D Rhainds J Hamelin, et al. 2006 The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications J Biol Chem 281 30561 30572 10.1074/jbc.M606495200 1:CAS:528:DC%2BD28XhtVCrsLrO 16912035
11. IK Kotowski A Pertsemlidis A Luke, et al. 2006 A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol Am J Hum Genet 78 410 422 10.1086/500615 1:CAS:528:DC%2BD28XitVWqtL8%3D 16465619
12. Z Zhao Y Tuakli-Wosornu TA Lagace, et al. 2006 Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote Am J Hum Genet 79 514 523 10.1086/507488 1:CAS:528: DC%2BD28Xpt1Snt70%3D 16909389
13. KM Timms S Wagner ME Samuels, et al. 2004 A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree Hum Genet 114 349 353 10.1007/s00439-003-1071-9 1:CAS:528:DC%2BD2cXhsFeqt7c%3D 14727179
14. RP Naoumova I Tosi D Patel, et al. 2005 Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response Arterioscler Thromb Vasc Biol 25 2654 2660 10.1161/01.ATV.0000190668.94752.ab 1:CAS:528:DC%2BD2MXht1Crt7vJ 16224054
15. B Herbert D Patel SN Waddington, et al. 2010 Increased secretion of lipoproteins in transgenic mice expressing human D374Y PCSK9 under physiological genetic control Arterioscler Thromb Vasc Biol 30 1333 1339 10.1161/ATVBAHA.110. 204040 1:CAS:528:DC%2BC3cXnsFGgtLs%3D 20448210 This is the first study to use the endogenous promoter to drive PCSK9 D374Y mutant expression and reproduce in mice the human phenotype of this highly deleterious defect
16. AJ Hooper AD Marais DM Tanyanyiwa JR Burnett 2007 The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population Atherosclerosis 193 445 448 10.1016/j.atherosclerosis.2006.08.039 1:CAS:528:DC%2BD2sXotVCltrw%3D 16989838
17. MS Brown JL Goldstein 2006 Biomedicine. Lowering LDL-not only how low, but how long? Science 311 1721 1723 10.1126/science.1125884 1:CAS:528: DC%2BD28XjtFWku7o%3D 16556829
18. SG Lakoski TA Lagace JC Cohen, et al. 2009 Genetic and metabolic determinants of plasma PCSK9 levels J Clin Endocrinol Metab 94 2537 2543 10.1210/jc.2009-0141 1:CAS:528:DC%2BD1MXosl2ksLo%3D 19351729
19. CC Huang M Fornage DM Lloyd-Jones, et al. 2009 Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study Circ Cardiovasc Genet 2 354 361 10.1161/CIRCGENETICS.108.828467 1:CAS:528:DC%2BD1MXhtFCgtr7L 20031607 This longitudinal study of normal young adults demonstrates the impact of LOF mutations on CAD risk factors in blacks and whites, shows the tracking with time of the cholesterol-lowering effect, and reveals an apoE by PCSK9 LOF mutation interaction
20. DM Hallman SR Srinivasan W Chen, et al. 2007 Relation of PCSK9 mutations to serum low-density lipoprotein cholesterol in childhood and adulthood (from The Bogalusa Heart Study) Am J Cardiol 100 69 72 10.1016/j.amjcard.2007.02.057 1:CAS:528:DC%2BD2sXntF2ktb8%3D 17599443
21. GD Norata K Garlaschelli L Grigore, et al. 2010 Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles Atherosclerosis 208 177 182 10.1016/j.atherosclerosis.2009.06.023 1:CAS:528:DC%2BC3cXkt1Cjsw%3D%3D 19619878 This work demonstrates that E670G polymorphism of the PCSK9 gene is associated with increased intima media thickness progression in the general population and reveals an interaction with apoE polymorphism
22. SN Chen CM Ballantyne AM Gotto Jr, et al. 2005 A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis J Am Coll Cardiol 45 1611 1619 10.1016/j.jacc.2005.01. 051 1:CAS:528:DC%2BD2MXktVOjtrw%3D 15893176
23. LA Hsu MS Teng YL Ko, et al. 2009 The PCSK9 gene E670G polymorphism affects low-density lipoprotein cholesterol levels but is not a risk factor for coronary artery disease in ethnic Chinese in Taiwan Clin Chem Lab Med 47 154 158 10.1515/CCLM.2009.032 1:CAS:528:DC%2BD1MXislarsL0%3D 19191720
24. D Evans FU Beil 2006 The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women BMC Med Genet 7 66 10.1186/1471-2350-7-66 16875509
25. E Polisecki I Peter M Robertson, et al. 2008 Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population Atherosclerosis 200 95 101 10.1016/j.atherosclerosis.2007.12.005 1:CAS:528:DC%2BD1cXhtVensbzK 18262190
26. AR Folsom JM Peacock E Boerwinkle 2009 Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease Atherosclerosis 202 211 215 10.1016/j.atherosclerosis.2008.03.009 1:CAS:528:DC%2BD1cXhsFajsb%2FK 18436227 This work reports an association of peripheral arterial disease prevalence, but not incidence, with PCSK9 LOF mutations
27. S Abboud PJ Karhunen D Lutjohann, et al. 2007 Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke PLoS ONE 2 e1043 10.1371/journal.pone.0001043 17940607
28. G Mayer S Poirier NG Seidah 2008 Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels J Biol Chem 283 31791 31801 10.1074/jbc.M805971200 1:CAS:528:DC%2BD1cXhtlCjsbvK 18799458
29. MJ Hayes RE Longbottom MA Evans SE Moss 2007 Annexinopathies Subcell Biochem 45 1 28 10.1007/978-1-4020-6191-2-1 1:STN:280:DC%2BD1c%2FktVahsA%3D%3D 18193632
30. G Dubuc A Chamberland H Wassef, et al. 2004 Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia Arterioscler Thromb Vasc Biol 24 1454 1459 10.1161/01.ATV.0000134621.14315.43 1:CAS:528:DC%2BD2cXmtValtLY%3D 15178557
31. KN Maxwell RE Soccio EM Duncan, et al. 2003 Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice J Lipid Res 44 2109 2119 10.1194/jlr.M300203-JLR200 1:CAS:528: DC%2BD3sXpslentr4%3D 12897189
32. JD Horton NA Shah JA Warrington, et al. 2003 Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes Proc Natl Acad Sci U S A 100 12027 12032 10.1073/pnas.1534923100 1:CAS:528:DC%2BD3sXotlGltbw%3D 14512514
33. G Dubuc M Tremblay G Pare, et al. 2010 A new method for measurement of total plasma PCSK9: clinical applications J Lipid Res 51 140 149 10.1194/jlr.M900273-JLR200 19571328 This work explores clinical applications of a new method that measures total plasma PCSK9 and demonstrates an additive effect of ezetimibe in raising plasma levels of PCSK9
34. HE Careskey RA Davis WE Alborn, et al. 2008 Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9 J Lipid Res 49 394 398 10.1194/jlr.M700437-JLR200 1:CAS:528:DC%2BD1cXhsVaitbk%3D 18033751
35. JS Troutt WE Alborn G Cao RJ Konrad 2010 Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels J Lipid Res 51 345 351 10.1194/jlr.M000620 1:CAS:528:DC%2BC3cXptVWnsA%3D%3D 19738285
36. J Mayne T Dewpura A Raymond, et al. 2008 Plasma PCSK9 levels are significantly modified by statins and fibrates in humans Lipids Health Dis 7 22 10.1186/1476-511X-7-22 18547436
37. G Lambert N Ancellin F Charlton, et al. 2008 Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment Clin Chem 54 1038 1045 10.1373/clinchem.2007.099747 1:CAS:528:DC%2BD1cXmvVarsLw%3D 18436719
38. S Kourimate C Le May C Langhi, et al. 2008 Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9 J Biol Chem 283 9666 9673 10.1074/jbc.M705831200 1:CAS:528:DC%2BD1cXkt1aksLo%3D 18245819
39. P Abidi Y Zhou JD Jiang J Liu 2005 Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine Arterioscler Thromb Vasc Biol 25 2170 2176 10.1161/01.ATV.0000181761.16341.2b 1:CAS:528:DC%2BD2MXhtVCltrjL 16100034
40. J Cameron T Ranheim MA Kulseth, et al. 2008 Berberine decreases PCSK9 expression in HepG2 cells Atherosclerosis 201 266 273 10.1016/j.atherosclerosis. 2008.02.004 1:CAS:528:DC%2BD1cXhsVGgsLfJ 18355829
41. H Li W Chen Y Zhou, et al. 2009 Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements J Lipid Res 50 820 831 10.1194/jlr.M800375-JLR200 1:CAS:528:DC%2BD1MXkvVSnurc%3D 19141871 This work identifies mRNA binding proteins that regulate the stability of LDLR mRNA induced by berberine through AU-rich elements, helping to explain its mechanism of action
42. H Li B Dong SW Park, et al. 2009 Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine J Biol Chem 284 28885 28895 10.1074/jbc.M109.052407 1:CAS:528:DC%2BD1MXht1Cmt73J 19687008 This study identifies HNF1α as a critical sequence motif for PCSK9 transcription and its regulation by berberine and reveals coordinate interactions between HNF1, SRE, and SREBP-2 in transactivation of the PCSK9 promoter
43. SW Park YA Moon JD Horton 2004 Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver J Biol Chem 279 50630 50638 10.1074/jbc.M410077200 1:CAS:528:DC%2BD2cXhtVWjsL%2FI 15385538
44. S Rashid DE Curtis R Garuti, et al. 2005 Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9 Proc Natl Acad Sci U S A 102 5374 5379 10.1073/pnas.0501652102 1:CAS:528:DC%2BD2MXjslaqsL8%3D 15805190
45. MJ Graham KM Lemonidis CP Whipple, et al. 2007 Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice J Lipid Res 48 763 767 10.1194/jlr.C600025-JLR200 1:CAS:528:DC%2BD2sXktFGhurg%3D 17242417
46. N Gupta N Fisker MC Asselin, et al. 2010 A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo PLoS ONE 5 e10682 10.1371/journal.pone.0010682 20498851
47. M Frank-Kamenetsky A Grefhorst NN Anderson, et al. 2008 Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates Proc Natl Acad Sci U S A 105 11915 11920 10.1073/pnas.0805434105 1:CAS:528:DC%2BD1cXhtVCnurjK 18695239
48. JC Chan DE Piper Q Cao, et al. 2009 A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates Proc Natl Acad Sci U S A 106 9820 9825 10.1073/pnas.0903849106 1:CAS:528:DC%2BD1MXotFGjs7k%3D 19443683
49. JF Thompson CL Hyde LS Wood, et al. 2009 Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the Treating to New Targets (TNT) cohort Circ Cardiovasc Genet 2 173 181 10.1161/CIRCGENETICS.108. 818062 1:CAS:528:DC%2BD1MXmvVyhtrY%3D 20031582
50. KE Berge L Ose TP Leren 2006 Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy Arterioscler Thromb Vasc Biol 26 1094 1100 10.1161/01.ATV.0000204337. 81286.1c 1:CAS:528:DC%2BD28XjsVersr0%3D 16424354