A development of oligonucleotide based DNA array for CYP2C9 genotyping for individual therapy in patients with valve replacement receiving warfarin therapy

开发基于寡核苷酸的 DNA 阵列，用于 CYP2C9 基因分型，用于接受华法林治疗的瓣膜置换术患者的个体化治疗

基本信息

批准号：
15590768
负责人：
NAKAI Kenji
金额：
$ 2.18万
依托单位：
Iwate Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Title I. The clinical use of oli0onucleotide based DNA array for CYP2C9^*3 and CYP2C9^*2 L'enotvPin2 in patients receiving warfarin therapyAbstract : 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 … More 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 populationsAbstract : 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

标题 I. 基于寡核苷酸的 DNA 阵列在接受华法林治疗的患者中用于 CYP2C9^*3 和 CYP2C9^*2 L'enotvPin2 的临床应用摘要：本研究的目的是验证 CYP2C9 单核苷酸多态性 (SNP) 在患者中的贡献接受华法林以避免栓塞和出血事件等副作用受试者包括 26 名接受瓣膜置换术的患者（19 名主动脉瓣置换患者）。使用最近开发的 OligoARRAY 系统测定 CYP2C9 基因 SNP 的基因分型，在自动分析仪系统上测量 CYP2C9 [CYP2C9^*2 突变体； (Argl44Cys), CYP2C9^*3突变体；ALO61C(Ile359Leu)]通过OligoARRAY直接测序验证，但在这26名野生患者中均未发现突变基因型。 AVR 组 (n='19) 的基因型为 1.6 ±0.2，MVR 组 (n4) 的基因型为 2±0.5， AVR&MVR 组的平均华法林剂量为 2.2±0.4（n=3），这些组的平均华法林剂量分别为 2.8±0.8 mg、3±0.7 mg 和 2.7±1.3 mg。用于可靠的 CYP2C9 基因分型，并且有可能在临床中常规使用，用于在华法林治疗前检测易感个体。 II. 日本和以色列人群中 CYP2C9^*2 (Ari'l44Cys) 和 CYP2C9^*3 (lle3S9Leu) 2enotvpes 的种族差异摘要：CYP2C9 有助于许多临床上重要的底物药物（例如华法林）的代谢。，使用新开发的方法评估了日本和以色列人群中 CYP2C9^*2 和 CYP2C9^*3 等位基因分布的种族差异基于寡核苷酸的 DNA 阵列 (OligoArray^R) 对 147 名日本人和 388 名以色列捐赠者（100 名德系犹太人、99 名也门犹太人、100 名摩洛哥犹太人和 89 名利比亚犹太人）进行了研究。CYP2C9^*2 [Argl44Cys (416 C> T)。 )，外显子 3] 和 CYP2C9^*3 (Ile359Leu (1061 A>C)，外显子7)基因型使用OligoArray^R确定。CYP2C9^*2基因型(CC/CT+TT)的频率在日本人中明显较低(1/0)(OR 0.02)，并且较高。与德系犹太人相比，利比亚犹太人 (0.697/0.303)（OR 2.13；95%CI 1.07-4.24） (0.83/0.17)、也门犹太人(0.899/0.101)、摩洛哥犹太人(0.81/0.19) CYP2C9^*3 基因型频率(AA/AC±CC)在日本人中显着较低(0.986/0.014)(OR 0.08)。），利比亚犹太人的比例更高（0.652/0.349）（OR 3.03； 95%CI 1.5-6.1) 和摩洛哥犹太人 (0.77/0.23)(OR 1.69; 95%CI 0.62-3.48) 与德系犹太人 (0.83/0.17)、也门犹太人 (0.899/0.101) 相比。 ^*2 (Argl44Cys) 和CYP2C9^*3 (Ile359Leu) 突变体在日本人群中很少见，并且在所检查的四个犹太族群中表现出不同的频率。