title: Cytochrome P450 (CYP2C9*2,*3) & vitamin-K epoxide reductase complex (VKORC1 -1639G<A) gene polymorphisms & their effect on acenocoumarol dose in patients with mechanical heart valve replacement.
abstract: OBJECTIVE
  Studies have demonstrated the effect of CYP2C9 (cytochrome P450) and VKORC1 (vitamin K epoxide reductase complex) gene polymorphisms on the dose of acenocoumarol. The data from India about these gene polymorphisms and their effects on acenocoumarol dose are scarce. The aim of this study was to determine the occurrence of CYP2C9*2,*3 and VKORC 1 -1639G>A gene polymorphisms and to study their effects on the dose of acenocoumarol required to maintain a target International Normalized Ratio (INR) in patients with mechanical heart valve replacement.
  
  
  METHODS
  Patients from the anticoagulation clinic of a tertiary care hospital in north India were studied. The anticoagulation profile, INR (International Normalized Ratio) values and administered acenocoumarol dose were obtained from the clinical records of patients. Determination of the CYP2C9*2,*3 and VKORC1 -1639G>A genotypes was done by PCR-RFLP (restriction fragment length polymorphism).
  
  
  RESULTS
  A total of 111 patients were studied. The genotype frequencies of CYP2C9 *1/*1,*1/*2,*1/*3 were as 0.883, 0.072, 0.036 and that of VKORC1 -1639G>A for GG, AG, and AA genotypes were 0.883, 0.090, and 0.027, respectively. The percentage of patients carrying any of the variant alleles of CYP2C9 and VKORC1 in heterozygous or homozygous form was 34% among those receiving a low dose of ≤20 mg/wk while it was 13.8 per cent in those receiving >20 mg/wk (P=0.014). A tendency of lower dose requirements was seen among carriers of the studied polymorphisms. There was considerable variability in the dose requirements of patients with and without variant alleles.
  
  
  CONCLUSIONS
  The study findings point towards the role of CYP2C9 and VKORC1 gene polymorphisms in determining the inter-individual dose variability of acenocoumarol in the Indian patients with mechanical heart valve replacement.
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Kaur
authors.forename: Farah
authors.initials: F
authors.lastname: Khan
authors.forename: Suraksha S
authors.initials: SS
authors.lastname: Agrawal
authors.forename: Aditya
authors.initials: A
authors.lastname: Kapoor
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Agarwal
authors.forename: Shubha R
authors.initials: SR
authors.lastname: Phadke
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000328:Adult; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005838:Genotype; D019918:Heart Valve Prosthesis Implantation; D006351:Heart Valves / Q000187:drug effects / Q000201:enzymology / Q000601:surgery; D006801:Humans; D007194:India; D019934:International Normalized Ratio; D008297:Male; D011110:Polymorphism, Genetic; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D000925:Anticoagulants; D054316:Biomarkers, Pharmacological; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol