| Co-Investigator(Kenkyū-buntansha) |
IZUMOTO Hirishi Iwate Medical University, Associate professor, 医学部, 講師 (10265150)
HABANO Wataru Iwate Medical University, Assistant professor, 医学部, 講師 (50332979)
NAKAI Keiko Iwate Medical University, Assistant professor, 医学部, 講師 (40227723)
MCRIYA Shogo Nisshinbo Industries, Inc. Research & Development center, 研究開発センター201G, 主任研究員
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Title I. The clinical use of oli0onucleotide based DNA array for CYP2C9^*3 and CYP2C9^*2 L'enotvPin2 in patients receiving warfarin therapy
Abstract : The aim of this investigation was to verify the contribution of CYP2C9 single nucleotide polymorphisms (SNPs) in patients receiving warfarin to avoid side effects such as embolic and hemorrhagic events. The subjects consisted of 26 patients with valve replacements (19 aortic valve, 4 mitral valve, 3 aortic and mitral valve), who were receiving warfarin therapy. Genotyping of CYP2C9 gene SNPs was determined using a recently developed OligoARRAY system. The international normalized ratio (PT-1NR) was measured on an auto-analyzer system using ISI value of 1.15. The accuracy of genotyping CYP2C9 [CYP2C9^*2 mutant; C416T (Argl44Cys), CYP2C9^*3 mutant; ALO61C (Ile359Leu)] by the OligoARRAY was verified by direct sequencing. However, no mutant genotypes were found in any of these 26 patients. The PT-FNR values for patients with the wild genotype
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was 1.6 ±0.2 in the AVR group (n='19), 2±0.5 in the MVR group (n4), and 2.2±0.4 in the AVR&MVR group (n=3). The average warfarin dose was 2.8 ± 0.8 mg, 3 ± 0.7 mg, and 2.7±1.3 mg, respectively for these group. In conclusion, the OligoARRAY was found to be convenient for the reliable genotyping of CYP2C9, and has the potential for routine use in the clinic for detecting susceptible individuals prior to warfarin treatment.
Title II. Ethnic differences in CYP2C9^*2 (Ari'l44Cys) and CYP2C9^*3 (lle3S9Leu) 2enotvpes in Japanese and Israeli populations
Abstract : CYP2C9 contributes to the metabolism of a number of clinically important substrate drugs such as warfarin. In the present study, ethnic differences in the CYP2C9^*2 and CYP2C9^*3 allele distribution in Japanese and Israeli populations were evaluated a using newly developed oligonucleotide based DNA array (OligoArray^R). The population studied consisted of 147 Japanese and 388 Israeli donors (100 Ashkenazi Jews, 99 Yemenite Jews, 100 Moroccan Jews and 89 Libyan Jews). The CYP2C9^*2 [Argl44Cys (416 C>T), exon 3] and CYP2C9^*3 (Ile359Leu (1061 A>C), exon 7) genotypes were determined using an OligoArray^R. The frequencies of CYP2C9^*2 genotype (CC/CT+TT) was significantly lower in Japanese (1/0)(OR 0.02), and was higher in Libyan Jews (0.697/0.303) (OR 2.13; 95%CI 1.07-4.24) compared with those in Ashkenazi Jews (0.83/0.17), Yemenite Jews (0.899/0.101), Moroccan Jews (0.81/0.19). The frequencies of CYP2C9^*3 genotype (AA/AC±CC) was significantly lower in Japanese (0.986/0.014)(OR 0.08), and was higher in Libyan Jews (0.652/0.349) (OR 3.03; 95%CI 1.5-6.1) and Moroccan Jews (0.77/0.23)(OR 1.69; 95%CI 0.62-3.48) compaered with those in Ashkenazi Jews (0.83/0.17), Yemenite Jews (0.899/0.101). Thus, the CYP2C9^*2 (Argl44Cys) and CYP2C9^*3 (Ile359Leu) mutant were rare in the Japanese population, and showed different frequencies in the four Jewish ethnic groups examined. Less
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