Perkütan koroner gı̇rı̇şı̇m sonrası klopı̇dogrel dı̇rencı̇nı̇n CYP2C9 ve CYP2C19 genlerı̇nı̇n kopya sayısı varyasyonu ile ı̇lı̇şkı̇sı̇

Yıl 2024, Cilt: 17 Sayı: 2, 262 - 270, 16.08.2024

Lokman Ayaz , Seyhan Şahin Hilal Sancar

Öz

Amaç: Bu çalışmada, CYP2C9 ve CYP2C19 genlerin kopya sayısı varyasyon (CNV) ile klopidogrel direnç mekanizması arasındaki ilişkinin araştırılması amaçlanmıştır. Yöntem: Çalışmaya, acil veya elektif stent implantasyonlu perkütan koroner girişim uygulanan 176 hasta dahil edildi. 600 mg klopidogrel yükleme dozu alan ve en az 5 gün süreyle standart doz (75 mg/gün) klopidogrel kullanan hastalardan alınan kan örneklerinde PFA-100 P2Y12 kiti ile kapanma zamanı ölçüldü. Hastalar kapanma zamanı değeri >106 saniye olanlar klopidogrele dirençli, ≤106 saniye olanlar klopidogrele dirençli olmayan olarak iki gruba ayrıldı. Hastalardan alınan tam kan örneklerinden Purelink Genomic DNA izolasyon kiti kullanılarak DNA izole edildi. CYP2C9 ve CYP2C19 genlerin kopya sayısı varyasyonları TaqMan kopya sayısı analiz kiti kullanılarak RT-PCR ile tespit edildi. Bulgular: Çalışmamızda %55.11 bireyde klopidogrel direnci yok iken, %44.89 bireyde ise klopidogrel direncine sahip olduğu saptadık. ). CYP2C19 (Hs05107177-intron 8) iki kopyaya sahip bireylerin bir ve üç kopyaya sahip bireylere göre sırası ile 4.91 ve 3,57 kat daha fazla klopidogrel ilaç̧ direnci geliştirme riskine sahip olduğu belirlendi. Sonuç: Elde ettiğimiz verilere göre, CYP2C19 (Hs05107177- intron 8) kopya sayısı varyasyonlarına sahip bireylerin klopidogrel direnci gelişme riskinin daha yüksek olduğunu göstermektedir.

Anahtar Kelimeler

Kopya sayısı varyasyon, CYP, klopidogrel direnci, perkütan koroner girişim

The relationship of CYP2C9 and CYP2C19 gene copy number variations with clopidogrel resistance after percutaneous coronary intervention

Öz

Aim: This study aimed to investigate the relationship between copy number variation (CNV) of CYP2C9 and CYP2C19 genes and the clopidogrel resistance mechanism. Method The study included 176 patients who underwent emergency or elective percutaneous coronary intervention with stent implantation. Closure time was measured with PFA-100 P2Y12 in blood samples taken from patients using clopidogrel with a standard dose (75 mg/day) for at least 5 days after 600 mg clopidogrel loading dose. The patients were divided into two groups closure time values >106 s as resistant to clopidogrel, ≤106 s were nonresistant to clopidogrel. DNA was isolated from whole blood samples taken from patients using the Purelink Genomic DNA isolation kit. CNVs of CYP2C9 and CYP2C19 genes were detected by RT-PCR using the TaqMan copy number assay kit. Results: In our study, we found that 55.11% of individuals did not have clopidogrel resistance, while 44.89% of individuals had clopidogrel resistance. In this study, it was shown that there was no statistically significant difference between CYP2C9 (Hs0518754), CYP2C9 (Hs05165291), CYP2C9 (Hs05165291), CYP2C19 (Hs02932336) and CYP2C19 (Hs05148033) CNVs and clopidogrel resistance (p˃0.05). It was determined that individuals with the two copies of CYP2C19 (Hs05107177-8 intron) have a 4.91- and 3.57-fold increased risk of developing clopidogrel drug resistance compared to the one and three copy, respectively. Conclusion: Our data show that individuals with CYP2C19 (Hs05107177- intron 8) copy number variations have a higher risk of developing clopidogrel resistance.

Anahtar Kelimeler

Copy number variation, CYP, clopidogrel resistance, cutaneous coronary intervention

Kaynakça

• Tao S, Tang X, Yu L, et al. Prognosis of coronary heart disease after percutaneous coronary intervention: a bibliometric analysis over the period 2004-2022. Eur J Med Res. 2023;28(1):311. doi: 10.1186/s40001-023-01220-5.
• Sun H, Qu Q, Chen ZF, et al. Impact of CYP2C19 variants on clinical efficacy of clopidogrel and 1-year clinical outcomes in coronary heart patients undergoing percutaneous coronary intervention. Front Pharmacol. 2016;24(7):453. doi: 10.3389/fphar.2016.00453
• Boden WE, O’Rourke RA, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. Engl J Med. 2007;356(15):1503–1516. doi: 10.1056/NEJMoa070829.
• Levine GN, Bates ER, John A. Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease. Circulation. 2016;134(10)123-55. doi: 10.1161/CIR.0000000000000404.
• Ali ZO, Bader L, Mohammed S, et al. Effect of CYP2C19 genetic variants on bleeding and major adverse cardiovascular events in a cohort of Arab patients undergoing percutaneous coronary intervention and stent implantation. Pharmacogenet Genomics. 2022;32(5):183–191. doi: 10.1097/FPC.0000000000000469
• Holmes DR, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clinical alert: ACCF/AHA clopidogrel clinical alert: Approaches to the FDA “boxed warning” a report of the American college of cardiology foundation task force on clinical expert consensus documents and the American heart association. Circulation. 2010;122:537–557.
• Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92–99. doi: 10.1124/dmd.109.029132.
• Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patientswith coronary stent placement. Circulation 2010;121(4):512-518. doi: 10.1161/CIRCULATIONAHA.109.885194.
• Frere C, Cuisset T, Morange PE, et al. Effect of cytochrome P450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008;101(8):1088-1093. doi: 10.1016/j.amjcard.2007.11.065.
• He Y, Hoskins JM, McLeod HL. Copy number variants in pharmacogenetic genes. Trends Mol Med. 2011;17(5):244-51. doi: 10.1016/j.molmed.2011.01.007.
• Craddock N, Hurles ME, Cardin N, et al. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010;464(7289):713–720. doi: 10.1038/nature08979.
• Johansson I, Ingelman-Sundberg M. CNVs of human genes and their implication in pharmacogenetics. Cytogenet Genome Res. 2008;123(1):195-204. doi: 10.1159/000184709.
• https://usa.healthcare.siemens.com/hemostasis/systems/pfa-100. Erişim tarihi 24.04.2018
• Karaźniewicz-Łada M, Danielak D, Główka F. Genetic and non-genetic factors affecting the response to clopidogrel therapy. Expert Opin Pharmacother. 2012;13(5):663-683. doi: 10.1517/14656566.2012.666524.
• Angiolillo DJ, Capranzano P, Desai B, et al. Impact of P2Y12 Inhibitory Effects Induced by Clopidogrel on Platelet Procoagulant Activity in Type 2 Diabetes Mellitus Patients. Thromb Res. 2009;124(3):318–322. doi: 10.1016/j.thromres.2008.10.001.
• Jastrzebska M, Marcinowska Z, Oledzki S, et al. Variable gender-dependent platelet responses to combined antiplatelet therapy in patients with stable coronary-artery disease. J Physiol Pharmacol. 2018,1;69(4):595–605. doi: 10.26402/jpp.2018.4.10.
• Gairolla J, Ahluwalia J, Khullar M, et al. Clopidogrel response in ischemic stroke patients: Is polymorphism or gender more important? Results of the CRISP study. J Clin Neurosci. 2020;76:81-86. doi: 10.1016/j.jocn.2020.04.038.
• Jang J, Lim J, Chang K, et al. A Comparison of INNOVANCE® PFA P2Y and VerifyNow P2Y12 Assay for the Assessment of Clopidogrel Resistance in Patients Undergoing Percutaneous Coronary Intervention. J Clin Lab Anal. 2012;26(4):262-266. doi: 10.1002/jcla.21515.
• al Awaida W, Ahmed AA, Hamza AA, Amber KI, Al-Ameer HJ, Jarrar Y, et al. Association of KDR rs1870377 genotype with clopidogrel resistance in patients with post percutaneous coronary intervention. Heliyon. 2021;7(2):e06251. doi: 10.1016/j.heliyon.2021.e06251.
• Zhang L, Lv Y, Dong J, Wang N, Zhan Z, Zhao Y, et al. Assessment of Risk Factors for Drug Resistance of Dual Anti Platelet Therapy After PCI. Clin Appl Thromb Hemost. 2022;28:1-9. doi: 10.1177/10760296221083674
• Saydam F, Değirmenci İ, Birdane A, Özdemir M, Ulus T, Özbayer C, et al. The CYP2C19*2 and CYP2C19*17 Polymorphisms play a Vital Role in Clopidogrel Responsiveness after Percutaneous Coronary Intervention: A Pharmacogenomics Study. Basic Clin Pharmacol Toxicol. 2017;121(1):29-36. doi: 10.1111/bcpt.12763.
• Sheng X yan, An H jie, He Y yang, Ye Y feng, Zhao J lan, Li S. High-Dose Clopidogrel versus Ticagrelor in CYP2C19 intermediate or poor metabolizers after percutaneous coronary intervention: A Meta-Analysis of Randomized Trials. Clin Pharm Ther. 2022;47(8):1112-1121. doi: 10.1111/jcpt.13665.
• Sun Y, Lu Q, Tao X, Cheng B, Yang G. Cyp2C19*2 Polymorphism Related to Clopidogrel Resistance in Patients With Coronary Heart Disease, Especially in the Asian Population: A Systematic Review and Meta-Analysis. Front Genet. 2020;11:576046. doi: 10.3389/fgene.2020.576046.
• Morales-Rosado JA, Goel K, Zhang L, et al. Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics. Cardiovasc Drugs Ther. 2021;35(3):549–59. doi: 10.1007/s10557-020-06988-w.
• Liu T, Yin T, Li Y, Song LQ, Yu J, Si R, et al. CYP2C19 polymorphisms and coronary heart disease risk factors synergistically impact clopidogrel response variety after percutaneous coronary intervention. Coron Artery Dis. 2014;25(5):412-420. doi: 10.1097/MCA.0000000000000092
• Kirac D, Erdem A, Avcilar T, Yesilcimen K, Guney AI, Emre A, et al.Effects of genetic factors to stent thrombosis due to clopidogrel resistance after coronary stent placement. Cell Mol Biol (Noisy-le-grand). 2016;62(1):51-55.