氯氮平疗效与细胞色素P4501A2酶基因多态性的关联研究

Novel mutation of the cytochrome P450 1A2 gene associated with the clinical response to clozapine in Chinese schizophrenic patients

目的 探讨氯氮平临床疗效的个体差异与其代谢酶细胞色素P4 5 0 1A2 (cytochromeP4 5 01A2 ,CYP1A2 )酶基因单核苷酸多态性的相关性。方法 对 99例符合CCMD 2 R精神分裂症诊断标准的患者和 10 6例健康对照者作病例 对照研究。分裂症患者给予氯氮平治疗 2个月 ,用阳性和阴性症状量表 (positiveandnegativesymptomscale,PANSS)评分评价氯氮平疗效。采用聚合酶链反应扩增及限制性片段长度多态性 (PCR RFLP)技术对CYP1A2 /C734A单核苷酸突变进行检测 ,分析氯氮平临床疗效的个体差异与其主要代谢酶CYP1A2 /C734A酶基因单核苷酸多态性的相关性。结果 (1)中国上海地区人群的CYP1A2 /C734A突变率为 6 1 3% ,患者组和健康对照组之间的基因型和等位基因频率无显著性差异 (χ2 =2 4 8,df=2 ;χ2 =1 80 ,df=1,P >0 0 5 ) ,CYP1A2 /C734A突变的多态性分布在分裂症的易感性及年龄、性别、发病年龄、病程、最大日用药剂量等其他相关因素中亦无显著性差异。 (2 )有阳性家族史的分裂症患者其纯合突变基因型 (AA)的频率较健康对照组有明显增多 (χ2 =5 2 8,df=1,P <0 0 5 )。 (3)CYP1A2 /C734A基因型、等位基因频率总体分布与氯氮平疗效之间无相关性 (χ2 =3 4 7,df=2 ;χ2 =2 77,df=1,P >0 0 5 )。 (4 )

Objective: To investigate the genetic association between mutations in cytochrome P450 1A2 (CYP1A2) gene and Chinese schizophrenia patients with clozapine response. Methods: A pharmacogenetic study is detected in 99 Chinese patients received a diagnosis of Chinese Classification and diagnostic Criteria for Mental Disorders, the Second Revised Edition (CCMD-2-R), for schizophrenia and 106 unrelated control subjects, the severity of symptoms and responses to clozapine were rated by the Positive and Negative Symptom Scale (PANSS), clozapine responders demonstrated a 20% reduction in PANSS rating. A single nucleotide polymorphism (SNP) at position 734 (C→A) of intron 1 of CYP1A2 gene were indentified by polymerase chain reaction with Bsp120I restricted endonuclease digestion. The data were analysed withχ2、ANOVA test. Results: (1)The incidence in Chinese population is 61.3%. No statistically significant differences between the patients and control group were detected with respect to either allele frequencies or genotypes distribution of CYP1A2; either, no association between CYP1A2/C734A and schizophrenia patients with sex, age, onset of age, family history, duration, ultimate dosage group as covariates. Chi-square analysis revealed significant difference between frequencies of the mutation homozygous with family history (genotype AA)and health controls (χ~2=5.28, df=1, P<0.05). Also the efficacies of clozapine in schizophrenia patients were not significantly differed among the 3 subgroups in either CYP1A2 genotype group. (χ~2=3.47, df=2; χ~2=2.77, df=1, P>0.05). The study only showed the wild-typed homozygous (genotype CC) were in tendency of higher in clozapine responders than the carrier with the mutated allele (genotype AC and AA) (χ~2=3.7721, P=0.055). Conclusion: The results demonstrate that mutation homozygous (genotype AA) is association with the schizophrenia patients with family history. Furthermore, the highly inducible with mutated allele in heterozygous is in marginal relation with the efficacy of Clozapine, it reveals that the single nucleotide polymorphism of CYP1A2/C734A have an important role in the interindividual variation of clozapine efficacy.