Association of gene polymorphisms with the risk of warfarin bleeding complications at therapeutic INR in patients with mechanical cardiac valves

作者：An S H; Lee K E; Chang B C; Gwak H S^*

来源：Journal of Clinical Pharmacy and Therapeutics, 2014, 39(3): 314-318.

DOI：10.1111/jcpt.12143

• bleeding
• thrombomodulin (THBD)
• genotype
• international normalized ratio (INR)
• cytochrome P450 subfamily 2C polypeptide 9 (CYP2C9)
• C-reactive protein (CRP)
• warfarin
• vitamin K epoxide reductase complex subunit 1 (VKORC1)

What is known and 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 center dot 0-3 center dot 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.
Results and discussion
Of 142 eligible patients, 21 patients (14 center dot 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 center dot 210, 95% CI: 0 center dot 050-0 center dot 875, P=0 center dot 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 center dot 575, 95% CI: 1 center dot 409-22 center dot 058, P=0 center dot 014). Variant VKORC1 and CYP2C9 genotypes did not confer a significant increase in the risk for bleeding complications.
What is new and 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.

• 出版日期2014-6