title: Influence of VKORC1 and CYP2C9 Polymorphisms on Daily Acenocoumarol Dose Requirement in South Indian Patients With Mechanical Heart Valves.
abstract: OBJECTIVE
  Chronic rheumatic heart disease (RHD) patients who undergo valve replacement with mechanical valves require lifelong anticoagulation. Acenocoumarol, a vitamin K antagonist has a narrow therapeutic range and wide inter-individual variability. Our aim was to investigate the influence of polymorphisms of VKORC1 and CYP2C9 genes on the mean daily dose requirement of acenocoumarol.
  
  
  METHODS
  205 chronic RHD patients, with mechanical heart valves and on acenocoumarol therapy, were recruited. Genotyping for VKORC1 (-1639G>A and 1173C>T) and CYP2C9 (*2 & *3 alleles) polymorphisms was done by PCR-RFLP. There was complete linkage disequilibrium between VKORC1 polymorphisms (r2= 0.98, D' = 1.0, LOD = 74.02). VKORC1 genotype distribution for GG/CC, GA/CT, and AA/TT were 57.6%, 36.1%, and 6.3%, respectively. CYP2C9 genotype distribution for *1/*1, *1/*3, *1/*2, *2/*2, and *2/*3 were 78.5%, 14.1%, 6.3%, 0.5%, and 0.5%, respectively. Patients with a wild type of both VKORC1 (-1639GG and 1173CC) and CYP2C9 gene variants required higher acenocoumarol dose compared to those with mutant genotype ( P = 0.023 and P = 0.008 respectively). On combined genotype analysis, patients having a combination of wild type of VKORC1 with wild type of CYP2C9 (44.4%) required higher daily dose compared to patients bearing heterozygous VKORC1 (-1639GA & 1173CT) with wild type of CYP2C9 (30.2%, P = 0.008).
  
  
  CONCLUSIONS
  Presence of a mutant allele of VKORC1 (-1639A & 1173T) and CYP2C9 genes increased the odds of requiring a lower mean dosage of acenocoumarol. Studying the combination of genotypes in RHD patients could predict acenocoumarol dose requirement more accurately.
authors.affiliation: 1 Department of Pathology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.
authors.forename: S R
authors.initials: SR
authors.lastname: Kalpana
authors.affiliation: 1 Department of Pathology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.
authors.forename: G
authors.initials: G
authors.lastname: Bharath
authors.affiliation: 2 Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India.
authors.forename: C N
authors.initials: CN
authors.lastname: Manjunath
authors.affiliation: 3 Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, Karnataka, India.
authors.forename: Rita
authors.initials: R
authors.lastname: Christopher
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006350:Heart Valve Prosthesis; D006801:Humans; D007194:India; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012214:Rheumatic Heart Disease / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy; D064417:Vitamin K Epoxide Reductases / Q000235:genetics*
chemical_list: D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol
keywords: CYP2C9; RHD; VKORC1; acenocoumarol; anticoagulation; gene polymorphisms