Kalp kapağı replasmanı sonrasında antikoagülan tedavide cyp2c9 gen polimorfizminin rolü
The role of cyp2c9 gene polymorphisms after heart valve replacement with anticoagulant therapy
Yazar: HATİCE YILDIRIM
Danışman: DOÇ.DR. LÜLÜFER TAMER
Mersin Üniversitesi / Sağlık Bilimleri Enstitüsü / Biyokimya Ana Bilim Dalı
Derece: Yüksek Lisans, 2006
Konu: Biyokimya = Biochemistry

Özet:
ABSTRACTTHE ROLE OF CYP2C9 GENE POLYMORPHISMS AFTER HEART VALVEREPLACEMENT WITH ANTICOAGULANT THERAPYValve replacement with valvular heart disease inevitable in certainconditions. Because of early calcific degeneration biological heart valves have ashort life time. Despite the mechanical valves have a long life time, anticoagulantmust be used because of tromboembolic complications. Coumadin is ananticoagulant agent used for the prevention of thromboembolic complications afterheart valve replacement. Bleeding is major adverse effect of coumadin. For thisreason, coumadin dose must be adjusted very well. Presently, the InternationalNormalized Ratio (INR) is used for coumadin dose adjustment. Coumadin ismetabolized by cytochrome P450 CYP2C9. In addition to the wild-type allele(CYP2C9*1), two allelic variants CYP2C9*2 and CYP2C9*3 have been identified.CYP2C9*2 is the result of cysteine substitution at arginine codon 144 andCYP2C9*3 is the result of a leucine substitution at isoleucine codon 359. Genepolymorphisms of CYP2C9 decrease coumadin metabolism so would increase thebleeding risk.The aim of the present study was to investigate the role of CYP2C9 genepolymorphisms after heart valve replacement in group of patients who are takingcoumadin. The study subjects were consisted of 74 patient with heart valcereplacement. DNA was extracted from blood samples. CYPC9*2, CYP2C9*3alleles were detected by using LightCycler-CYP2C9 mutation detection kit by realtime PCR method with LightCycler instrument.The results of our show that CYP2C9 genotype is associated with the meanmaintenance dose of warfarin. In our study, we found that patients havingCYP2C9*2 and CYP2C9*3 genotype have lower dose of coumadin according topatients having wild type genotype (CYP2C9*2 p=0.0296, CYP2C9*3 p=0.022). Inaddition to combine association of CYP2C9*2 and CYP2C9*3 genotype coumadindose and INR levels were investigated and we found that patients having bothforms of CYP2C9*2 and CYP2C9*3 heterozygous (CYP2C9*2/*3) require lowercoumadin dose than patients having wild type genotype (p=0.001).Our results showed that CYP2C9 genotyping before anticoagulant therapycan be a guideline in the patients with valve replacement for coumadin therapyand it may be useful for devoloping dosing protocols particularly at the onset oftherapy.Key Words: Valve replacement, mechanic heart valve, CYP2C9, coumadin.

Abstract:
ABSTRACTTHE ROLE OF CYP2C9 GENE POLYMORPHISMS AFTER HEART VALVEREPLACEMENT WITH ANTICOAGULANT THERAPYValve replacement with valvular heart disease inevitable in certainconditions. Because of early calcific degeneration biological heart valves have ashort life time. Despite the mechanical valves have a long life time, anticoagulantmust be used because of tromboembolic complications. Coumadin is ananticoagulant agent used for the prevention of thromboembolic complications afterheart valve replacement. Bleeding is major adverse effect of coumadin. For thisreason, coumadin dose must be adjusted very well. Presently, the InternationalNormalized Ratio (INR) is used for coumadin dose adjustment. Coumadin ismetabolized by cytochrome P450 CYP2C9. In addition to the wild-type allele(CYP2C9*1), two allelic variants CYP2C9*2 and CYP2C9*3 have been identified.CYP2C9*2 is the result of cysteine substitution at arginine codon 144 andCYP2C9*3 is the result of a leucine substitution at isoleucine codon 359. Genepolymorphisms of CYP2C9 decrease coumadin metabolism so would increase thebleeding risk.The aim of the present study was to investigate the role of CYP2C9 genepolymorphisms after heart valve replacement in group of patients who are takingcoumadin. The study subjects were consisted of 74 patient with heart valcereplacement. DNA was extracted from blood samples. CYPC9*2, CYP2C9*3alleles were detected by using LightCycler-CYP2C9 mutation detection kit by realtime PCR method with LightCycler instrument.The results of our show that CYP2C9 genotype is associated with the meanmaintenance dose of warfarin. In our study, we found that patients havingCYP2C9*2 and CYP2C9*3 genotype have lower dose of coumadin according topatients having wild type genotype (CYP2C9*2 p=0.0296, CYP2C9*3 p=0.022). Inaddition to combine association of CYP2C9*2 and CYP2C9*3 genotype coumadindose and INR levels were investigated and we found that patients having bothforms of CYP2C9*2 and CYP2C9*3 heterozygous (CYP2C9*2/*3) require lowercoumadin dose than patients having wild type genotype (p=0.001).Our results showed that CYP2C9 genotyping before anticoagulant therapycan be a guideline in the patients with valve replacement for coumadin therapyand it may be useful for devoloping dosing protocols particularly at the onset oftherapy.Key Words: Valve replacement, mechanic heart valve, CYP2C9, coumadin.