Abstract
Warfarin is widely prescribed for patients with the risk of thromboembolism around the world. The inter-individual and inter-racial differences in appropriate dosage depend highly on age, body weight, and genetic factors. A lot of studies including genome-wide association studies revealed that vitamin K epoxide reductase complex, subunit 1 (VKORC1) G-1639A and Cytochrome P450 (CYP) 2C9 A1075C are the most strong genetic factors for determining warfarin effects in Asians and Africans. Since we developed a quick and inexpensive genotyping method, polymerase chain reaction with confronting two-pair primers (PCR-CTPP), the method was applied for these genotypes to examine the possibility to clinical use. Subjects were 436 examinees (117 males and 319 females, aged 32 to 85 years) who attended a health checkup program in Japan. The PCR-CTPP for VKORC1 G-1639A and CYP2C9 A1075C was conducted for the subjects, as well as the samples genotyped by DigiTag2 method. The allele frequencies of VKORC1 G-1639A were 0.085 for G and 0.915 for A, and those of CYP2C9 A1075C were 0.979 for A and 0.021 for C, being in Hardy-Weinberg equilibrium (p = 0.658 and p = 0.514, respectively). These frequencies were similar to those reported in the HapMap project. Genotyping for both SNPs by PCR-CTPP was replicated by DigiTag2 method. Our results indicated that the PCR-CTPP could be one of the alternative methods for genotyping VKORC1 G-1639A and CYP2C9 A1075C for Asians and Africans with similar allele frequencies to Japanese.
Highlights
Warfarin is one of the most widely prescribed anticoagulants to prevent venous and arterial thromboembolism
The promoter with VKORC1 -1639G major allele showed 44% increase in promoter activity compared with the promoter with -1639A minor allele (Rieder et al 2005). These findings have proved that VKORC1 G-1639A is a single nucleotide polymorphism (SNP) to be one of the most important factors for explaining individual differences in warfarin dosage
The genotype information (*1*1, *1*3, and *3*3: each of two samples) of Shizuoka area obtained by DigiTag2 method was accorded with that obtained by PCR-CTPP
Summary
Warfarin is one of the most widely prescribed anticoagulants to prevent venous and arterial thromboembolism. This medicine has a very narrow therapeutic range; the high doses increase the risk of bleeding and the low doses do not prevent thromboembolic disorders such as stroke. It is well known that warfarin exhibits large inter-individual and inter-racial differences in the dosage for an appropriate effect. It needs a relatively long time in practice to determine the appropriate dosage for each patient within the optimal prothrombin time measured with an international normalized ratio (PT-INR) range.
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