Login Register Cart 0
Generic placeholder image

Current Pharmacogenomics and Personalized Medicine

Editor-in-Chief

ISSN (Print): 1875-6921
ISSN (Online): 1875-6913

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

PCSK9 A/G (rs505151) Gene Polymorphism and its Expression at the Molecular Level in Patients with Coronary Artery Disease

Author(s): Kamna Srivastava*, Shelly Aggarwal, Rajiv Narang and Daman Saluja

Volume 19, Issue 2, 2022

Published on: 20 October, 2022

Page: [66 - 76] Pages: 11

DOI: 10.2174/1875692119666220930161000

Price: $65

Abstract

Background: PCSK9 (Proprotein convertase subtilisin/kexin type 9) plays a key role in cholesterol homeostasis and Coronary artery disease (CAD). Many studies have extrapolated the association of the PCSK9 gene with low-density lipoprotein cholesterol (LDL-C) levels and CAD but with contradicting results. No such study is available stating the intergenotypic variations in the levels of expression of PCSK9 and LDL-C and their correlations with CAD risk factors in patients with CAD.

Objective: We aim to explore the association of PCSK9 A/G (rs505151) polymorphism and its expression at mRNA and protein levels in patients with CAD. It also investigates how LDL-C, PCSK9, BMI, and systolic blood pressure (SBP) levels in patients with CAD and in healthy participants relate to the PCSK9 intergenotypic variation.

Methods: Angiographically confirmed CAD patients [n=250] and controls [n=250] were genotyped by PCR followed by RFLP techniques. Real-time PCR and Western Blot methods were used to investigate PCSK9's differential expression.

Results: Odds ratio being the index of association, revealed a statistically significant association of PCSK9 A/G (rs505151), A Vs G= 4.94 [1.37-7.79] polymorphism with CAD. In patients with the GG genotype, there is a correlation between higher PCSK9 gene expression and circulating LDL-C levels.

Conclusion: Our study shows a significant association of PCSK9 gene polymorphism with CAD. We also observed an increased expression of the PCSK9 gene in patients with the G allele. In our study, PCSK9 A/G (rs505151) gene and LDL-C emerged as independent risk factors. More follow-up research is required to determine whether upregulated PCSK9 gene expression can act as a prognostic marker for CAD.

Keywords: Coronary artery disease, genetic polymorphism, low-density lipoprotein receptor, proprotein convertase, subtilisin/kexin type 9, SBP, LDL-C.

« Previous Next »
Graphical Abstract

[1]
Abifadel, M.; Varret, M.; Rabès, J.P.; Allard, D.; Ouguerram, K.; Devillers, M.; Cruaud, C.; Benjannet, S.; Wickham, L.; Erlich, D.; Derré, A.; Villéger, L.; Farnier, M.; Beucler, I.; Bruckert, E.; Chambaz, J.; Chanu, B.; Lecerf, J.M.; Luc, G.; Moulin, P.; Weissenbach, J.; Prat, A.; Krempf, M.; Junien, C.; Seidah, N.G.; Boileau, C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet., 2003, 34(2), 154-156.
[http://dx.doi.org/10.1038/ng1161] [PMID: 12730697]
[2]
Maxwell, K.N.; Soccio, R.E.; Duncan, E.M.; Sehayek, E.; Breslow, J.L. Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J. Lipid Res., 2003, 44(11), 2109-2119.
[http://dx.doi.org/10.1194/jlr.M300203-JLR200] [PMID: 12897189]
[3]
Benjannet, S.; Rhainds, D.; Essalmani, R.; Mayne, J.; Wickham, L.; Jin, W.; Asselin, M.C.; Hamelin, J.; Varret, M.; Allard, D.; Trillard, M.; Abifadel, M.; Tebon, A.; Attie, A.D.; Rader, D.J.; Boileau, C.; Brissette, L.; Chrétien, M.; Prat, A.; Seidah, N.G. NARC-1/PCSK9 and its natural mutants: Zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem., 2004, 279(47), 48865-48875.
[http://dx.doi.org/10.1074/jbc.M409699200] [PMID: 15358785]
[4]
Park, S.W.; Moon, Y.A.; Horton, J.D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem., 2004, 279(48), 50630-50638.
[http://dx.doi.org/10.1074/jbc.M410077200] [PMID: 15385538]
[5]
Poirier, S.; Mayer, G.; Benjannet, S.; Bergeron, E.; Marcinkiewicz, J.; Nassoury, N.; Mayer, H.; Nimpf, J.; Prat, A.; Seidah, N.G. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem., 2008, 283(4), 2363-2372.
[http://dx.doi.org/10.1074/jbc.M708098200] [PMID: 18039658]
[6]
Leigh, S.E.A.; Leren, T.P.; Humphries, S.E. Commentary PCSK9 variants: A new database. Atherosclerosis, 2009, 203(1), 32-33.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.02.006] [PMID: 19249440]
[7]
Zhao, Z.; Tuakli-Wosornu, Y.; Lagace, T.A.; Kinch, L.; Grishin, N.V.; Horton, J.D.; Cohen, J.C.; Hobbs, H.H. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet., 2006, 79(3), 514-523.
[http://dx.doi.org/10.1086/507488] [PMID: 16909389]
[8]
Abifadel, M.; Guerin, M.; Benjannet, S.; Rabès, J.P.; Le Goff, W.; Julia, Z.; Hamelin, J.; Carreau, V.; Varret, M.; Bruckert, E.; Tosolini, L.; Meilhac, O.; Couvert, P.; Bonnefont-Rousselot, D.; Chapman, J.; Carrié, A.; Michel, J.B.; Prat, A.; Seidah, N.G.; Boileau, C. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis, 2012, 223(2), 394-400.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.04.006] [PMID: 22683120]
[9]
Cohen, J.C.; Boerwinkle, E.; Mosley, T.H., Jr; Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med., 2006, 354(12), 1264-1272.
[http://dx.doi.org/10.1056/NEJMoa054013] [PMID: 16554528]
[10]
Abifadel, M.; Rabès, J.P.; Devillers, M.; Munnich, A.; Erlich, D.; Junien, C.; Varret, M.; Boileau, C. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum. Mutat., 2009, 30(4), 520-529.
[http://dx.doi.org/10.1002/humu.20882] [PMID: 19191301]
[11]
Sabatine, M.S.; Giugliano, R.P.; Wiviott, S.D.; Raal, F.J.; Blom, D.J.; Robinson, J.; Ballantyne, C.M.; Somaratne, R.; Legg, J.; Wasserman, S.M.; Scott, R.; Koren, M.J.; Stein, E.A. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N. Engl. J. Med., 2015, 372(16), 1500-1509.
[http://dx.doi.org/10.1056/NEJMoa1500858] [PMID: 25773607]
[12]
Ding, K.; Kullo, I.J. Molecular population genetics of PCSK9: A signature of recent positive selection. Pharmacogenet. Genomics, 2008, 18(3), 169-179.
[http://dx.doi.org/10.1097/FPC.0b013e3282f44d99] [PMID: 18300938]
[13]
Hachem, A.; Hariri, E.; Saoud, P.; Lteif, C.; Lteif, L.; Welty, F. The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in cardiovascular homeostasis: A non-systematic literature review. Curr. Cardiol. Rev., 2017, 13(4), 274-282.
[PMID: 28782494]
[14]
Chandra, S.; Narang, R.; Sreenivas, V.; Bhatia, J.; Saluja, D.; Srivastava, K. Association of angiotensin II type 1 receptor (A1166C) gene polymorphism and its increased expression in essential hypertension: A case-control study. PLoS One, 2014, 9(7), e101502.
[http://dx.doi.org/10.1371/journal.pone.0101502] [PMID: 24992666]
[15]
Feng, Q.; Wei, W.Q.; Chung, C.P.; Levinson, R.T.; Bastarache, L.; Denny, J.C.; Stein, C.M. The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy. Pharmacogenomics J., 2017, 17(2), 204-208.
[http://dx.doi.org/10.1038/tpj.2016.3] [PMID: 26902539]
[16]
Huang, C.C.; Fornage, M.; Lloyd-Jones, D.M.; Wei, G.S.; Boerwinkle, E.; Liu, K. Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: The coronary artery risk development in young adults study. Circ. Cardiovasc. Genet., 2009, 2(4), 354-361.
[http://dx.doi.org/10.1161/CIRCGENETICS.108.828467] [PMID: 20031607]
[17]
Chen, S.N.; Ballantyne, C.M.; Gotto, A.M., Jr; Tan, Y.; Willerson, J.T.; Marian, A.J. 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., 2005, 45(10), 1611-1619.
[http://dx.doi.org/10.1016/j.jacc.2005.01.051] [PMID: 15893176]
[18]
Evans, D.; Beil, F.U. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med. Genet., 2006, 7(1), 66.
[http://dx.doi.org/10.1186/1471-2350-7-66] [PMID: 16875509]
[19]
Norata, G.D.; Garlaschelli, K.; Grigore, L.; Raselli, S.; Tramontana, S.; Meneghetti, F.; Artali, R.; Noto, D.; Cefalù, A.B.; Buccianti, G.; Averna, M.; Catapano, A.L. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis, 2010, 208(1), 177-182.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.06.023] [PMID: 19619878]
[20]
Hsu, L.A.; Teng, M.S.; Ko, Y.L.; Chang, C.J.; Wu, S.; Wang, C.L.; Hu, C.F. 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., 2009, 47(2), 154-158.
[http://dx.doi.org/10.1515/CCLM.2009.032] [PMID: 19191720]
[21]
Reddy, S.; Kaur, N.; Singh, J. A novel study to examine the association of PCSK9 rs505151 polymorphism and coronary artery disease in north Indian population. J. Genet., 2018, 97(5), 1371-1378.
[http://dx.doi.org/10.1007/s12041-018-1043-4] [PMID: 30555085]

Rights & Permissions Print Cite
Article Metrics
22
3
© 2024 Bentham Science Publishers | Privacy Policy