title: Association of gene polymorphisms with the risk of warfarin bleeding complications at therapeutic INR in patients with mechanical cardiac valves.
abstract: OBJECTIVE
  Pharmacogenetic studies of the genetic regulation of warfarin dose requirement have been reported, but few have been on the bleeding complications at therapeutic international normalized ratio (INR). This study aimed to evaluate the effect of gene polymorphisms of CYP2C9, VKORC1, thrombomodulin (THBD) and C-reactive protein (CRP) on the risk of bleeding complications of warfarin at therapeutic INR in Korean patients with mechanical cardiac valves.
  
  
  METHODS
  A retrospective warfarin pharmacogenetic association study was performed. One hundred and forty-two patients with mechanical cardiac valves who were on warfarin anticoagulation therapy and maintained INR levels of 2·0-3·0 for 3 consecutive time intervals were followed up. CYP2C9 rs1057910, VKORC1 rs9934438, CRP rs1205, THBD rs1042580 and THBD rs3176123 were genotyped. The association between genotypes and warfarin bleeding complications was evaluated using logistic regression analysis, adjusted for demographic and clinical factors.
  
  
  CONCLUSIONS
  Of 142 eligible patients, 21 patients (14·8%) had bleeding complications at therapeutic INR. Patients with the G allele in THBD rs1042580 (AG or GG) had a lower risk of bleeding than patients with the AA genotype (adjusted OR: 0·210, 95% CI: 0·050-0·875, P = 0·032). The THBD rs3176123 polymorphism did not show any association with bleeding. For CRP rs1205, patients with the A allele (GA or AA genotype) had a higher risk of bleeding than patients with the GG genotype (adjusted OR: 5·575, 95% CI: 1·409-22·058, P = 0·014). Variant VKORC1 and CYP2C9 genotypes did not confer a significant increase in the risk for bleeding complications.
  
  
  CONCLUSIONS
  As expected, no association could be found between bleeding complications and two dose-related genes (CYP2C9*3 and VKORC1 rs9934438). In contrast, our results suggest that two genetic markers (THBD rs1042580 and CRP rs1205) could be predictors of bleeding complications of warfarin at normal INR. Given the retrospective study design and the relatively small sample size, our hypothesis requires further independent validation using more robust prospective designs. However, additional retrospective studies similar to ours but in populations with different genetic backgrounds should also be useful.
authors.affiliation: College of Pharmacy & Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: An
authors.forename: K E
authors.initials: KE
authors.lastname: Lee
authors.forename: B C
authors.initials: BC
authors.lastname: Chang
authors.forename: H S
authors.initials: HS
authors.lastname: Gwak
mesh_terms: D000368:Aged; D000483:Alleles; D000925:Anticoagulants / Q000009:adverse effects*; D002097:C-Reactive Protein / Q000235:genetics; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D005260:Female; D005838:Genotype; D006350:Heart Valve Prosthesis; D006470:Hemorrhage / Q000139:chemically induced* / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D012189:Retrospective Studies; D018180:Thrombomodulin / Q000235:genetics; D064417:Vitamin K Epoxide Reductases / Q000235:genetics; D014859:Warfarin / Q000009:adverse effects*
chemical_list: D000925:Anticoagulants; D018180:Thrombomodulin; D014859:Warfarin; D002097:C-Reactive Protein; D065729:Cytochrome P-450 CYP2C9; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases
keywords: C-reactive protein (CRP); bleeding; cytochrome P450 subfamily 2C polypeptide 9 (CYP2C9); genotype; international normalized ratio (INR); thrombomodulin (THBD); vitamin K epoxide reductase complex subunit 1 (VKORC1); warfarin