PCSK9 GENE PARTICIPATES IN THE DEVELOPMENT
OF PRIMARY DYSLIPIDEMIAS
Matías-Pérez D1, Pérez-Santiago AD1, Sánchez Medina MA1, Alpuche Osorno JJ2, García-Montalvo IA1
*Corresponding Author: Dr. Iván A. García-Montalvo, Division of Postgraduate Studies and Research,
Tecnológico Nacional de México/Instituto Tecnológico de Oaxaca, Oaxaca City, Oaxaca, México. Av.
Víctor Bravo Ahuja No. 125, Esq. Calzada Tecnológico Oaxaca, Oaxaca. Tel./Fax: +52-951-501-5016.
E-mail: ivan.garcia@itoaxaca.edu.mx
page: 5
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REFERENCES
1. Díaz-Aragón A, Fernández-Barros CL, Enciso-
Muñoz JM, Ceballos-Reyes G, Gutiérrez-Salmeán G,
León Hernández FJ, et al.e. Posicionamiento en torno
al diag-nóstico y tratamiento de las dislipidemias. Rev
Mex Cardiol. 2018; 29(3): 148-168.
2. World Health Organization. Cardiovascular diseases
(CVDs). [http://www.who.int/news-room/fact-sheets/
detail/cardiovasculard-diseases-(cvds); accessed June
13 2020].
3. Barquera S, Pedroza-Tobías A, Medina C, Hernández-
Barrera L, Bibbins-Domingo K, Lozano R, et al.
Global overview of the epidemiology of atherosclerotic
cardiovascular disease. Arch Med Res. 2015;
46(5): 328-338.
4. Nowbar AN, Gitto M, Howard JP, Francis DP, Al-
Lamee R. Mortality from ischemic heart disease. Circ
Cardiovasc Qual Outcomes. 2019; 12(6): e005375.
5. Martinez-Sanchez C, Borrayo G, Carrillo J, Juarez U,
Quintanilla J, Jerjes-Sanchez C. Clinical management
and hospital outcomes of acute coronary syndrome
patients in Mexico: The Third National Registry of
Acute Coronary Syndromes (RENASICA III). Arch
Cardiol México. 2016; 86(3): 221-232.
6. Canalizo-Miranda E, Favela-Pérez EA, Salas-Anaya
JA, Gómez-Díaz R, Jara-Espino R, Del L, et al. Guía
de práctica clínica Diagnóstico y tratamiento de las
dislipidemias. Rev Med Inst Mex Seguro Soc. 2013;
51(6): 700-709.
7. McEvoy JW, Whelton SP, Blumenthal RS. Dyslipidemia.
In: Bakris GL, Sorrentino MJ, Editors.
Hypertension: A Companion to Braunwald’s Heart
Disease, 3rd ed. Chicago, IL, USA: Elsevier, 2018:
353-360.
8. Urbina EM, Daniels SR. Hyperlipidemia. In: Slap
GB, Editor. Adolescent Medicine. Philadelphia, PA,
USA: Mosby, 2008: 90-96.
9. Hurtubise J, McLellan K, Durr K, Onasanya O,
Nwabuko D, Ndisang JF. The different facets of dyslipidemia
and hypertension in atherosclerosis. Curr
Atheroscler Rep. [Internet] 2016; 18(12): 82.
10. Matías-Pérez D, Pérez-Campos E, Antonio García-
Montalvo I, Antonio I, Montalvo G. A genetic view
of familial hypercholesterolemia. Nutr Hosp. 2015;
32(6): 2421-2426.
11. Smith LC, Massey JB, Sparrow JT, Gotto AM,
Pownall HJ. Structure and dynamics of human plasma
lipoproteins. In: Bakris GL, Sorrentino MJ, Editors.
Supramolecular Structure and Function. Boston, MA,
USA: Springer US; 1983; 205-244.
12. Barter PJ, Brewer HB, Chapman MJ, Hennekens CH,
Rader DJ, Tall AR. Cholesteryl ester transfer protein.
Arterioscler Thromb Vasc Biol. 2003; 23(2): 160-167.
13. Yamashita T, Lakota K, Taniguchi T, Yoshizaki A,
Sato S, Hong W, et al. An orally-active adiponectin
receptor agonist mitigates cutaneous fibrosis, inflammation
and microvascular pathology in a murine
model of systemic sclerosis. Sci Rep. 2018; 8(1):
11843.
14. Huang Q, Qin L, Dai S, Zhang H, Pasula S, Zhou
H, et al. AIP1 suppresses atherosclerosis by limiting
hyperlipidemia-induced inflammation and vascular
endothelial dysfunction. Arterioscler Thromb Vasc
Biol. 2013; 33(4): 795-804.
15. Kuivenhoven JA, Hegele RA. Mining the genome for
lipid genes. Biochim Biophys Acta. 2014; 1842(10):
1993-2009.
16. 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(5): 1378-1387.
17. Akioyamen LE, Genest J, Shan SD, Reel RL, Albaum
JM, Chu A, et al. Estimating the prevalence of heterozygous
familial hypercholesterolaemia: A systematic
review and meta-analysis. BMJ Open. 2017; 7(9):
e016461.
18. Nassoury N, Blasiole DA, Tebon Oler A, Benjannet
S, Hamelin J, Poupon V, et al. The cellular trafficking
of the secretory proprotein convertase PCSK9 and its
dependence on the LDLR. Traffic. 2007; 8(6): 718-732.
19. Luo Y, Warren L, Xia D, Jensen H, Sand T, Petras
S, et al. Function and distribution of circulating human
PCSK9 expressed extrahepatically in transgenic
mice. J Lipid Res. 2009; 50(8): 1581-1588.
20. Dijk W, Le May C, Cariou B. Beyond LDL: What
role for PCSK9 in triglyceride-rich lipoprotein metabolism?
Trends Endocrinol Metab. 2018; 29(6):
420-434.
21. Lalanne F, Lambert G, Amar MJA, Chétiveaux M,
Zaïr Y, Jarnoux AL, et al. Wild-type PCSK9 inhibits
LDL clearance but does not affect apoB-containing
lipoprotein production in mouse and cultured cells.
J Lipid Res. 2005; 46(6): 1312-1319.
22. Seidah NG, Benjannet S, Wickham L, Marcinkiewicz
J, Bélanger Jasmin S, Stifani S, et al. The secretory
proprotein convertase neural apoptosis-regulated
convertase 1 (NARC-1): Liver regeneration and
neuronal differentiation. Proc Natl Acad Sci USA.
2003; 100(3): 928-933.
23. Gustafsen C, Kjolby M, Nyegaard M, Mattheisen
M, Lundhede J, Buttenschøn H, et al. The hypercho lesterolemia-risk gene SORT1 facilitates PCSK9 secretion.
Cell Metab. 2014; 19(2): 310-318.
24. Schmidt RJ, Beyer TP, Bensch WR, Qian YW, Lin A,
Kowala M, et al. Secreted proprotein convertase subtilisin/
kexin type 9 reduces both hepatic and extrahepatic
low-density lipoprotein receptors in vivo. Biochem
Biophys Res Commun. 2008; 370(4): 634-640.
25. Marian AJ. PCSK9 as a therapeutic target in atherosclerosis.
Curr Atheroscler Rep. 2010; 12(3): 151-154.
26. Seidah NG. PCSK9 as a therapeutic target of dyslipidemia.
Expert Opin Ther Targets. 2009; 13(1):
19-28.
27. Sabatine MS. Proprotein convertase subtilisin/ kexin
type 9 (PCSK9) inhibitors: Comparing and contrasting
guidance across the Atlantic. Eur Heart J. 2017;
38(29): 2256-2258.
28. Li S, Zhang Y, Xu R-X, Guo Y-L, Zhu C-G, Wu N-Q,
et al. Proprotein convertase subtilisin-kexin type 9
as a biomarker for the severity of coronary artery
disease. Ann Med. 2015; 47(5): 386-393.
29. Alonso R, Mata P, Muñiz O, Fuentes-Jimenez F, Díaz
JL, Zambón D, et al. PCSK9 and lipoprotein (a) levels
are two predictors of coronary artery calcification in
asymptomatic patients with familial hypercholesterolemia.
Atherosclerosis. 2016; 254: 249-253.
30. Kim JH. Letter: Serum levels of PCSK9 are associated
with coronary angiographic severity in patients
with acute coronary syndrome (Diabetes Metab J.
2018;42:207-14). Diabetes Metab J. 2018; 42(4):
348-349.
31. Tang Z, Li T, Peng J, Zheng J, Li T, Liu L, et al.
PCSK9: A novel inflammation modulator in atherosclerosis?
J Cell Physiol. 2019;234(3): 2345-2355.
32. Hopkins PN, Defesche J, Fouchier SW, Bruckert E,
Luc G, Cariou B, et al. Characterization of autosomal
dominant hypercholesterolemia caused by PCSK9
cain of function mutations and its specific treatment
with alirocumab, a PCSK9 monoclonal antibody. Circ
Cardiovasc Genet. 2015; 8(6): 823-831.
33. 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(2): 161-165.
34. 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(1): 29-36.
35. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L,
Grishin NV, Horton JD, et al. Molecular characterization
of loss-of-function mutations in PCSK9 and
identification of a compound heterozygote. Am J
Hum Genet. 2006; 79(3): 514-523.
36. Abifadel M, Varret M, Rabès J-P, Allard D, Ouguerram
K, Devillers M, et al. Mutations in PCSK9 cause autosomal
dominant hypercholesterolemia. Nat Genet.
2003; 34(2): 154-156.
37. Timms KM, Wagner S, Samuels ME, Forbey K,
Goldfine H, Jammalapati S, et al. A mutation in PCSK9
causing autosomal-dominant hypercholesterolemia in
a Utah pedigree. Hum Genet. 2004; 114(4): 349-353.
38. 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(4): 1089-1093.
39. Leren TP. Mutations in the PCSK9 gene in Norwegian
subjects with autosomal dominant hypercholesterolemia.
Clin Genet. 2004; (4): 419-422.
40. 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(9): 1161-1169.
41. Bourbon M, Alves AC, Medeiros AM, Silva S, Soutar
AK. Familial hypercholesterolaemia in Portugal.
Atherosclerosis. 2008; 196(2): 633-642.
42. 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(5): 497.
43. 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(2): 659-666.
44. Abifadel M, Rabès J-P, Devillers M, Munnich A,
Erlich D, Junien C, et al. Mutations and polymorphisms
in the proprotein convertase subtilisin kexin 9
(PCSK9) gene in cholesterol metabolism and disease.
Hum Mutat. 2009; 30(4): 520-529.
45. Iacocca MA, Wang J, Sarkar S, Dron JS, Lagace
T, McIntyre AD, et al. Whole-gene duplication of
PCSK9 as a novel genetic mechanism for severe familial
hypercholesterolemia. Can J Cardiol. 2018;
34(10): 1316-1324. 46. Zambrano T, Hirata MH, Cerda Á, Dorea EL, Pinto
GA, Gusukuma MC, et al. Impact of 3’UTR genetic
variants in PCSK9 and LDLR genes on plasma lipid
traits and response to atorvastatin in Brazilian subjects:
A pilot study. Int J Clin Exp Med. 2015; 8(4):
5978-5988.
47. Robles-Osorio L, Huerta-Zepeda A, Ordóñez ML,
Canizales-Quinteros S, Díaz-Villaseñor A, Gutiérrez-
Aguilar R, et al. Genetic heterogeneity of autosomal
dominant hypercholesterolemia in Mexico. Arch Med
Res. 2006; 37(1): 102-108.
48. Mehta R, Zubirán R, Martagón AJ, Vazquez-Cárdenas
A, Segura-Kato Y, Tusié-Luna MT, et al. The panorama
of familial hypercholesterolemia in Latin
America: A systematic review. J Lipid Res. 2016;
57(12): 2115-2129.
49. Garg A, Fazio S, Duell PB, Baass A, Udata C, Joh T,
et al. Molecular characterization of familial hypercholesterolemia
in a North American cohort. J Endocr
Soc. 2020; 4(1): 1-16.
50. Sánchez-Hernández RM, Tugores A, Nóvoa FJ, Brito-
Casillas Y, Expósito-Montesdeoca AB, Garay P, et
al. The island of Gran Canaria: A genetic isolate for
familial hypercholesterolemia. J Clin Lipidol. 2019;
13(4): 618-626.
51. Abifadel M, Rabès JP, Jambart S, Halaby G, Gannagé-
Yared MH, Sarkis A, et al. The molecular basis of
familial hypercholesterolemia in Lebanon: Spectrum
of LDLR mutations and role of PCSK9 as a modifier
gene. Hum Mutat. 2009;30(7): E682-E691.
52. Yang KC, Su YN, Shew JY, Yang KY, Tseng WK, Wu
CC, et al. LDLR and ApoB are major genetic causes
of autosomal dominant hypercholesterolemia in a
taiwanese population. J Formos Med Assoc. 2007;
106(10): 799-807.
53. Pisciotta L, Oliva CP, Cefalù AB, Noto D, Bel-locchio
A, Fresa R, et al. Additive effect of mutations in
LDLR and PCSK9 genes on the phenotype of familial
hypercholesterolemia. Atherosclerosis. 2006; 186(2):
433-440.
54. Noguchi T, Katsuda S, Kawashiri M-A, 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(1): 166-172.
55. Roche-Molina M, Sanz-Rosa D, Cruz FM, García-
Prieto J, López S, Abia R, et al. Induction of sustained
hypercholesterolemia by single adeno-associated
virus-mediated gene transfer of mutant hPCSK9.
Arterioscler Thromb Vasc Biol. 2015; 35(1): 50-59.
56. Bjørklund MM, Hollensen AK, Hagensen MK,
Dagnæs-Hansen F, Christoffersen C, Mikkelsen JG,
et al. Induction of atherosclerosis in mice and hamsters
without germline genetic engineering. Circ Res.
2014; 114(11): 1684-1689.
57. Goettsch C, Hutcheson JD, Hagita S, Rogers MA,
Creager MD, Pham T, et al. A single injection of
gain-of-function mutant PCSK9 adeno-associated
virus vector induces cardiovascular calcification in
mice with no genetic modification. Atherosclerosis.
2016; 251: 109-118.
58. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier
S, Lazure C, et al. Gene inactivation of proprotein convertase
subtilisin/kexin type 9 reduces atherosclerosis
in mice. Circulation. 2012; 125(7): 894-901.
59. Al-Mashhadi RH, Sørensen CB, Kragh PM,
Christoffersen C, Mortensen MB, Tolbod LP, et al.
Familial hypercholesterolemia and atherosclerosis in
cloned minipigs created by DNA transposition of a
human PCSK9 gain-of-function mutant. Sci Transl
Med. 2013; 5(166): 1-10.
60. Hedayat AF, Park K-H, Kwon T-G, Woollard JR,
Jiang K, Carlson DF, et al. Peripheral vascular atherosclerosis
in a novel PCSK9 gain-of-function mutant
Ossabaw miniature pig model. Transl Res. 2018; 192:
30-45.
61. Miller M, Kwiterovich PO. Isolated low HDLcholesterol
as an important risk factor for coronary
heart disease. Eur Heart J. 1990; 11(suppl H): 9-14.
62. Puntoni M, Sbrana F, Bigazzi F, Sampietro T. Tangier
disease: Epidemiology, pathophysiology, and management.
Am J Cardiovasc Drugs. 2012; 12(5): 303-311.
63. Savel J, Lafitte M, Pucheu Y, Pradeau V, Tabarin A,
Couffinhal T. Very low levels of HDL cholesterol and
atherosclerosis, a variable relationship--a review of
LCAT deficiency. Vasc Health Risk Manag. 2012; 8:
357-361.
64. Yuan F, Guo L, Park KH, Woollard JR, Taek-Geun
K, Jiang K, et al. Ossabaw pigs with a PCSK9 fainof-
function mutation develop accelerated coronary
atherosclerotic lesions: A novel model for preclinical
studies. J Am Heart Assoc. 2018; 7(6): e006207.
65. Duff CJ, Hooper NM. PCSK9: An emerging target
for treatment of hypercholesterolemia. Expert Opin
Ther Targets. 2011; 15(2): 157-168.
66. Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy
SM, McCarthy BJ. Association between a specific
apolipoprotein B mutation and familial defective
apolipoprotein B-100. Proc Natl Acad Sci USA. 1989;
86(2): 587-591. 67. Myant NB. Familial defective apolipoprotein B-100:
A review, including some comparisons with familial
hypercholesterolaemia. Atherosclerosis. 1993; 104(1-
2): 1-18.
68. Dugaiczyk A, Haron JA, Stone EM, Dennison OE,
Rothblum KN, Schwartz RJ. Cloning and sequencing
of a deoxyribonucleic acid copy of glyceraldehyde-
3-phosphate dehydrogenase messenger ribonucleic
acid isolated from chicken muscle. Biochemistry.
1983; 22(7): 1605-1613.
69. Eden ER, Naoumova RP, Burden JJ, McCarthy MI,
Soutar AK. Use of homozygosity mapping to identify
a region on chromosome 1 bearing a defective
gene that causes autosomal recessive homozygous
hypercholesterolemia in two unrelated families. Am
J Hum Genet. 200; 68(3): 653-660.
70. Soutar AK, Naoumova RP, Traub LM. Genetics, clinical
phenotype, and molecular cell biology of autosomal
recessive hypercholesterolemia. Arterioscler
Thromb Vasc Biol. 2003; 23(11): 1963-1970.
71. Canizales-Quinteros S, Aguilar-Salinas CA, Huertas-
Vázquez A, Ordóñez-Sánchez ML, Rodríguez-Torres
M, Venturas-Gallegos JL, et al. A novel ARH splice
site mutation in a Mexican kindred with autosomal
recessive hypercholesterolemia. Hum Genet. 2005;
116(1-2): 114-120.
72. Harada K, Miyamoto Y, Morisaki H, Ohta N,
Yamanaka I, Kokubo Y, et al. A novel Thr56Met
mutation of the autosomal recessive hypercholesterolemia
gene associated with hypercholesterolemia. J
Atheroscler Thromb. 2010; 17(2): 131-140.
73. Awan Z, Choi HY, Stitziel N, Ruel I, Bamimore MA,
Husa R, et al. APOE p.Leu167del mutation in familial
hypercholesterolemia. Atherosclerosis. 2013; 231(2):
218-222.
74. Sharifi M, Futema M, Nair D, Humphries SE.
Polygenic hypercholesterolemia and cardiovascular
disease risk. Curr Cardiol Rep. 2019; 21(6): 43.
75. Stoll M, Dell’Oca N. Genética de la hipercolesterolemia
familiar. Rev Urug Cardiol. 2019; 34(3): 324-332.
76. Bourbon M, Alves AC, Sijbrands EJ. Low-density
lipoprotein receptor mutational analysis in diagnosis
of familial hypercholesterolemia. Curr Opin Lipidol.
2017; 8(2): 120-129.
77. Graham CA, McIlhatton BP, Kirk CW, Beattie ED,
Lyttle K, Hart P, et al. Genetic screening protocol for
familial hypercholesterolemia which includes splicing
defects gives an improved mutation detection
rate. Atherosclerosis. 2005; 182(2): 331-340.
78. Nose D, Hori M, Miyamoto Y, Imaizumi S, Harada-
Shiba M, Saku K, et al. Discontinuation of LDL
apheresis with evolocumab in an FH patient with a
duplication of exon 2-6 in the LDLR gene. J Cardiol
Cases. 2019; 19(2): 55-58.
79. Cheng S, Wu Y, Wen W, An M, Gao Y, Wang L, et
al. Independent severe cases of heterozygous familial
hypercholesterolemia caused by the W483X and
novel W483G mutations in the low-density lipoprotein
receptor gene that were clinically diagnosed as
homozygous cases. Genet Test Mol Biomarkers.
2019; 23(6): 401-408.
80. 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(7):
1544-1568.
81. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz
J, et al. Accumulation of dietary cholesterol in sitosterolemia
caused by mutations in adjacent ABC
transporters. Science. 2000; 290(5497): 1771-1775.
82. Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC.
Identification by whole-genome resequencing of gene
defect responsible for severe hypercholesterolemia.
Hum Mol Genet. 2010; 19(22): 4313-4318.
83. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka
H, et al. Identification of a gene, ABCG5, important
in the regulation of dietary cholesterol absorption.
Nat Genet. 2001; 27(1): 79-83.
84. Soumian S, Albrecht C, Davies AH, Gibbs RG.
ABCA1 and atherosclerosis. Vasc Med. 2005; 10(2):
109-119.
85. Olson MV. Human genetic individuality. Annu Rev
Genomics Hum Genet. 2012; 13: 1-27.
86. Ho Hong S, Rhyne J, Zeller K, Miller M. Novel
ABCA1 compound variant associated with HDL
cholesterol deficiency. Biochim Biophys Acta. 2002;
1587(1): 60-64.
87. Ahmadzadeh A, Azizi F. Genes Associated with low
serum high-density lipoprotein cholesterol. Arch Iran
Med. 2014; 17(6): 444-450.
88. Sabatine MS. PCSK9 inhibitors: Clinical evidence
and implementation. Nat Rev Cardiol. 2019; 16(3):
155-165.
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