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Evaluation of PCSK9 E670G and N425S Gene Variations in Coronary Heart Disease in Turkish Population

Year 2018, Issue: 4, 345 - 360, 20.04.2018

Abstract

Aim: Coronary artery disease (CAD) due to atherosclerosis
is a multifactorial disease resulting from the interaction of numerous genetic
and environmental factors.
In developed
countries, it is among the diseases with highest rates of mortality and
morbidity. Proprotein convertase subtilisin/kexin 9 (PCSK9), plays an important
role for cholesterol homoeostasis via inducing post-transcriptional degradation
of Low-density lipoprotein-Receptor (LDLR).Since PCSK9’s first discovery
in 2003, studies focusing on PCSK9 continue without slowing down and now PCSK9
is a candidate as a new therapeutic target in atherosclerosis. However, little
is known about the genetic variants of PCSK9 and its influence on Low Density
Lipoprotein – cholesterol (LDL-C) in Turkish population. Mutations in the PCSK9
gene have been associated with both hypocholesterolemia and
hypercholesterolemia through ‘loss-of-function’ and ‘gain-of-function’
mechanisms, respectively. Our aim was to investigate PCSK9 N425S (rs28362261) and E670G
(23968A>G) (rs 505151) gene
polymorphisms in regard to their effects on serum lipoprotein level and
development of CHD.

Method: PCR-RFLP (Polymerase Chain Reaction-Restriction
Fragment Length Polymorphism) method is used for determination of PCSK9
variants.

Findings: In the patient group, frequency of PCSK9 E670G mutant T allele is higher than controls. Our findings indicate
that these variants might be an independent risk factors in development of CHD.
In the patient group, we observed the PCSK9
E670G normal A allele is associated with increased serum total-cholesterol
level.







Conclusion: In conclusion we suggest that the
PCSK9 gene variants
might pose a
risk in susceptibility to CHD, since PCSK9 has detrimental effects on serum
lipids.

References

  • Thirumalai T, Tamilselvan N, David E. Hypolipidemic activity of Piper betel in high fat diet induced hyperlipidemic rat. J Acute Disease. 2014;(3):131–135. https://doi.org/10.1016/S2221-6189(14)60029-9.
  • Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–156. doi: 10.1038/ng1161.
  • Lalanne F, Lambert G, Amar MJ, et al. Wild-type PCSK9 inhibits LDL clearance but does not affect apo B-containing lipoprotein production in mouse and cultured cells. J Lipid Res. 2005;46(6):1312-1319. doi: 10.1194/jlr.M400396-JLR200.
  • Park SW, Moon YA, Horton JD. 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. doi: 10.1074/jbc.M410077200.
  • Seidah NG, Benjannet S, Wickham L, 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. doi: 10.1073/pnas.0335507100.
  • Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24(8):1454-1459. doi: 10.1161/01.ATV.0000134621.14315.43.
  • Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102(6):2069–2074. doi: 10.1073/pnas.0409736102.
  • Benjannet S, Rhainds D, Essalmani R, et al. 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. doi: 10.1074/jbc.M409699200.
  • 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(18):7100-7115. doi: 10.1073/pnas.0402133101.
  • Horton JD, Shah NA, Warrington JA, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA. 2003;100(21):12027-12032. doi: 10.1073/pnas.1534923100.
  • Leren, TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65(5):419–422. doi: 10.1111/j.0009-9163.2004.0238.x.
  • Sun XM, Eden ER, Tosi I, 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. doi: 10.1093/hmg/ddi128.
  • Timms KM, Wagner S, Samuels ME, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet. 2004;114(4):349–353. doi: 10.1007/s00439-003-1071-9.
  • Zhao ZY, Tuakli-Wosornu TA, Lagace L, 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. doi: 10.1086/507488.
  • Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161–165. doi: 10.1038/ng1509.
  • Welder G, Zineh I, Pacanowski MA, et al. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res. 2010;51(9):2714-2721. doi: 10.1194/jlr.M008144.
  • Evans D, Beil FU. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med Genet. 2006;(31):7-66. https://doi.org/10.1186/1471-2350-7-66.
  • Pisciotta L, Priore Oliva C, Cefalù AB, et al. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis. 2006;186(2):433-440. doi: 10.1016/j.atherosclerosis.2005.08.015.
  • Hampton EN, Knuth MW, Li J, et al. The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc Natl Acad Sci USA. 2007;104(37):14604-14609. doi: 10.1073/pnas.0703402104.
  • Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282(25):18602-18612. doi: 10.1074/jbc.M702027200.
  • Fasano T, Sun XM, Patel DD, Soutar AK. Degradation of LDLR protein mediated by ‘Gain of function’ PCSK9 mutants in normal and ARH cells. Atherosclerosis. 2009;203(1):166–171. doi: 10.1016/j.atherosclerosis. 2008.10.027.
  • Chen SN, Ballantyne CM, Gotto AM Jr, et al. 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. doi: 10.1016/j.jacc.2005.01.051.
  • Abboud S, Karhunen PJ, Lütjohann D, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS ONE. 2007;2(10):e1043. https://doi.org/10.1371/journal.pone.0001043.

Koroner Kalp Hastalarında PCSK9 E670G ve N425S Gen Varyasyonlarının Etkisinin Türk Toplumunda Değerlendirilmesi

Year 2018, Issue: 4, 345 - 360, 20.04.2018

Abstract

Amaç: Aterosklerozdan kaynaklanan Koroner Arter Hastalığı (KAH)
çeşitli genetik ve çevresel etmenlerin etkileşiminden kaynaklanan
multifaktöriyel bir hastalıktır. Gelişmiş ülkelerde en yüksek mortalite ve
morbidite nedenlerindendir. Proprotein subtilisin keksin tip-9 (PCSK9), Düşük
Yoğunluklu Lipoprotein Reseptörü (Low-density lipoprotein-Receptor / LDLR)'nün
post-transkripsiyonel degredasyonunu indükleyerek kolesterol hemostazında
önemli bir rol oynamaktadır. PCSK9'un ilk keşfedildiği 2003 yılından bu yana
çalışmalar hız kesmeden devam etmiş ve artık anti-PCSK9 monoklonal antikorları
ateroskleroz tedavisinde yeni bir hedef olarak sunulmuştur. Ancak Türk
popülasyonunda PCSK9'un genetik varyasyonları ve LDL-kolesterol (LDL-K)
üzerindeki etkisi hakkında çok az bilgi vardır. PCSK9 genindeki mutasyonlar
sırasıyla fonksiyon kaybı ve fonsiyon kazanımı mekanizmaları aracılığı ile hem
hipokolesterolemi hemde hiperkolesterolemi ile ilişkilidir. Çalışmamızda; PCSK9
fonksiyon kazanımı ile ilişkili N425S (rs28362261) ve E670G (23968A>G) (rs 505151) gen polimorfizmlerinin serum
lipoprotein düzeyi ve KAH gelişimindeki etkilerinin belirlenmesi amaçlanmıştır.



Yöntem: 64 hasta ve 50 kontrol’ün PCSK9 E670G ve N425S varyantının belirlenmesi için PCR-RFLP
(Polimeraz Zincir Reaksiyonu-Restriksiyon Parça Uzunluk Polimorfizmi) yöntemi
kullanılmıştır.



Bulgular: Koroner arter hastalarında PCSK9 E670G mutant T alleli frekansı kontrol grubuna göre daha yüksek gözlenmiştir. Verilerimiz bu varyantın
koroner kalp hastalığı gelişiminde bağımsız risk faktörü olabileceğini  önermektedir. Koroner arter hastalarında PCSK9 E670G normal A alleli yüksek serum
total-kolesterol düzeyi ile ilişkili bulunmuştur.
PCSK9
N425S polimorfizmi dağılımlarında hasta ve kontrol gruplarında sadece NN normal
homozigot genotipi gözlenmiştir.



Sonuç: PCSK9 genindeki E670G varyantının serum lipid profili
üzerindeki olumsuz etkileriyle koroner kalp hastalığı gelişiminde risk oluşturabileceğini
göstermektedir. 

References

  • Thirumalai T, Tamilselvan N, David E. Hypolipidemic activity of Piper betel in high fat diet induced hyperlipidemic rat. J Acute Disease. 2014;(3):131–135. https://doi.org/10.1016/S2221-6189(14)60029-9.
  • Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154–156. doi: 10.1038/ng1161.
  • Lalanne F, Lambert G, Amar MJ, et al. Wild-type PCSK9 inhibits LDL clearance but does not affect apo B-containing lipoprotein production in mouse and cultured cells. J Lipid Res. 2005;46(6):1312-1319. doi: 10.1194/jlr.M400396-JLR200.
  • Park SW, Moon YA, Horton JD. 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. doi: 10.1074/jbc.M410077200.
  • Seidah NG, Benjannet S, Wickham L, 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. doi: 10.1073/pnas.0335507100.
  • Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24(8):1454-1459. doi: 10.1161/01.ATV.0000134621.14315.43.
  • Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102(6):2069–2074. doi: 10.1073/pnas.0409736102.
  • Benjannet S, Rhainds D, Essalmani R, et al. 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. doi: 10.1074/jbc.M409699200.
  • 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(18):7100-7115. doi: 10.1073/pnas.0402133101.
  • Horton JD, Shah NA, Warrington JA, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA. 2003;100(21):12027-12032. doi: 10.1073/pnas.1534923100.
  • Leren, TP. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet. 2004;65(5):419–422. doi: 10.1111/j.0009-9163.2004.0238.x.
  • Sun XM, Eden ER, Tosi I, 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. doi: 10.1093/hmg/ddi128.
  • Timms KM, Wagner S, Samuels ME, et al. A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree. Hum Genet. 2004;114(4):349–353. doi: 10.1007/s00439-003-1071-9.
  • Zhao ZY, Tuakli-Wosornu TA, Lagace L, 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. doi: 10.1086/507488.
  • Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37(2):161–165. doi: 10.1038/ng1509.
  • Welder G, Zineh I, Pacanowski MA, et al. High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res. 2010;51(9):2714-2721. doi: 10.1194/jlr.M008144.
  • Evans D, Beil FU. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med Genet. 2006;(31):7-66. https://doi.org/10.1186/1471-2350-7-66.
  • Pisciotta L, Priore Oliva C, Cefalù AB, et al. Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia. Atherosclerosis. 2006;186(2):433-440. doi: 10.1016/j.atherosclerosis.2005.08.015.
  • Hampton EN, Knuth MW, Li J, et al. The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc Natl Acad Sci USA. 2007;104(37):14604-14609. doi: 10.1073/pnas.0703402104.
  • Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem. 2007;282(25):18602-18612. doi: 10.1074/jbc.M702027200.
  • Fasano T, Sun XM, Patel DD, Soutar AK. Degradation of LDLR protein mediated by ‘Gain of function’ PCSK9 mutants in normal and ARH cells. Atherosclerosis. 2009;203(1):166–171. doi: 10.1016/j.atherosclerosis. 2008.10.027.
  • Chen SN, Ballantyne CM, Gotto AM Jr, et al. 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. doi: 10.1016/j.jacc.2005.01.051.
  • Abboud S, Karhunen PJ, Lütjohann D, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS ONE. 2007;2(10):e1043. https://doi.org/10.1371/journal.pone.0001043.
There are 23 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Articles
Authors

Ayşegül Başak Akadam Teker

Erhan Teker This is me

Özlem Kurnaz Gömleksiz This is me

Hülya Yılmaz Aydoğan

Publication Date April 20, 2018
Acceptance Date March 6, 2018
Published in Issue Year 2018 Issue: 4

Cite

JAMA Akadam Teker AB, Teker E, Kurnaz Gömleksiz Ö, Yılmaz Aydoğan H. Koroner Kalp Hastalarında PCSK9 E670G ve N425S Gen Varyasyonlarının Etkisinin Türk Toplumunda Değerlendirilmesi. IGUSABDER. 2018;:345–360.

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