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

Title I. The clinical use of oli0onucleotide based DNA array for CYP2C9^*3 and CYP2C9^*2 L'eotvPin2 in patients receiving warfarin therapyAbstract : The aim of this investigation was to verify the contribution of CYP2C9 single nuclearotide polymorphisms (SNPs) in patients receiving warfarin to avoid side effects such as embolic and hemorrhagic events.受试者由26例替代瓣膜置换术（19例主动脉瓣，4个二尖瓣，3个主动脉瓣和二尖瓣）组成，他们正在接受华法林治疗。 CYP2C9基因SNP的基因分型使用最近开发的寡聚系统确定。国际归一化比率（PT-1NR）使用ISI值1.15在自动分析仪系统上测量。基因分型CYP2C9的准确性[CYP2C9^*2突变体； C416T（argl44cys），cyp2c9^*3突变体；通过直接测序验证了寡聚架的ALO61C（ILE359LEU）]。但是，在这26例患者中，尚未发现突变基因型。 AVR组的野生基因型患者的PT-FNR值是1.6±0.2（n = '19），MVR组为2±0.5（N4），AVR＆MVR组为2.2±0.4（n = 3）。总的来说，华法林的平均剂量为2.8±0.8 mg，3±0.7 mg和2.7±1.3 mg，总而言之，发现寡聚剂对于CYP2C9的可靠基因分型很方便，并且有可能在临床中进行常规使用，以检测临床前的临床前敏感人。 CYP2C9^*2（ARI'L44CYS）和CYP2C9^*3（LLE3S9LEU）的种族差异在日本和以色列人群中的2notVES删除：CYP2C9：CYP2C9有助于多种临床上重要的替代药物（如Warfararin）的代谢。在本研究中，使用新开发的基于寡核苷酸的DNA阵列（寡聚物^r）评估了CYP2C9^*2和CYP2C9^*3的种族差异。所研究的人口包括147名日本和388个以色列捐助者（100名Ashkenazi犹太人，99位也门犹太人，100名摩洛哥犹太人和89位利比亚犹太人）。 CYP2C9^*2 [argl44Cys（416 c> t），外显子3]和CYP2C9^*3（ILE359LEU（1061 A> C），外显子7）基因型是使用寡聚式^r确定的。日语（1/0）（或0.02）的CYP2C9^*2基因型（CC/CT+TT）的频率明显较低，在利比亚犹太人中较高（0.697/0.303）（OR 2.13; 95％CI 1.07-4.24），与Ashkenazi犹太人相比（0.83/0.83/0.17），（0.899/0.101），摩洛哥犹太人（0.81/0.19）。日语（0.986/0.014）（或0.08）的CYP2C9^*3基因型（AA/AC±CC）的频率明显较低，在利比亚犹太人（0.652/0.349）（0.652/0.349）（OR 3.03; 95％CI 1.5-6.1）和0.5-6.1）和摩洛哥犹太人（0.6.5-6.1）（0.6.5-6.1）（0.6.5-6.1）（0.23％）（0.23％）（95％）（或1.23）（或95％）（或95％）（或95％）； 0.62-3.48）与Ashkenazi犹太人（0.83/0.17），也门犹太人（0.899/0.101）进行比较。那就是CYP2C9^*2（ARGL44CYS）和CYP2C9^*3（ILE359LEU）突变体在日本人群中很少见，并且在检查的四个犹太族裔中显示出不同的频率。较少的