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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

标题一本研究的目的是验证CYP 2C 9单核苷酸多态性（SNP）在华法林治疗患者中的作用，以避免栓塞和出血事件等副作用。受试者包括26例接受华法林治疗的瓣膜置换术患者（19例主动脉瓣，4例二尖瓣，3例主动脉瓣和二尖瓣）。使用最近开发的OligoARRAY系统确定CYP 2C 9基因SNPs的基因分型。使用ISI值1.15在自动分析仪系统上测量国际标准化比值（PT-1 NR）。通过直接测序验证了OligoARRAY对CYP 2C 9 [CYP 2C 9 ^*2突变体; C416 T（Argl 44 Cys），CYP 2C 9 ^*3突变体; ALO 61 C（Ile 359 Leu）]基因分型的准确性。然而，在这26例患者中没有发现突变基因型。野生基因型患者的PT-FNR值 ...更多信息主动脉瓣置换术组（n = 19）为1.6 ±0.2，二尖瓣置换术组（n = 4）为2±0.5，主动脉瓣置换术和二尖瓣置换术组（n=3）为2.2±0.4。华法林的平均剂量分别为2.8 ± 0.8 mg、3 ± 0.7 mg和2.7±1.3 mg。总之，发现OligoARRAY便于CYP 2C 9的可靠基因分型，并且具有在临床上常规使用的潜力，用于在华法林治疗之前检测易感个体。日本和以色列人群中CYP 2C 9 ^*2（Ari'l44 Cys）和CYP 2C 9 ^*3（lle 3S 9 Leu）2 enotvpes的种族差异摘要：CYP 2C 9参与了许多临床重要底物药物如华法林的代谢。在本研究中，使用新开发的基于寡核苷酸的DNA阵列（OligoArray^R）评估了日本和以色列人群中CYP 2C 9 ^*2和CYP 2C 9 ^*3等位基因分布的种族差异。研究人群包括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）。使用OligoArray^R确定CYP 2C 9 ^*2 [Argl 44 Cys（416 C>T），外显子3]和CYP 2C 9 ^*3（Ile 359 Leu（1061 A>C），外显子7）基因型。CYP 2C 9 ^*2基因型频率（CC/CT+TT）在日本人中显著较低（1/0）（OR 0.02），利比亚犹太人更高（0.697/0.303）（OR 2.13; 95%CI 1.07-4.24）与德系犹太人（0.83/0.17）、也门犹太人（0.899/0.101）、摩洛哥犹太人（0.81/0.19）相比。CYP 2C 9 ^*3基因型频率（AA/AC±CC）在日本人中显著较低（0.986/0.014）（OR 0.08），利比亚犹太人更高（0.652/0.349）（OR 3.03; 95%CI 1.5-6.1）和摩洛哥犹太人与德系犹太人（0.83/0.17）、也门犹太人（0.899/0.101）比较，差异有统计学意义（OR 1.69; 95%CI 0.62-3.48）。因此，CYP 2C 9 ^*2（Argl 44 Cys）和CYP 2C 9 ^*3（Ile 359 Leu）突变体在日本人群中很少见，在所研究的四个犹太种族群体中显示出不同的频率。少