CYP2D6基因多态性与利培酮治疗精神分裂症疗效的关联研究

The correlation between CYP2D6 gene polymorphisms and clinical response of risperidone treatment in Chinese Han schizophrenia patients

目的 探讨CYP2D6基因多态性与利培酮治疗精神分裂症临床疗效间的关系.方法 114例汉族精神分裂症患者（患者组）经单一利培酮治疗12周,应用PANSS、个人与社会表现量表（Personal and Social Performance Scale,PSP）、瑞文标准推理测验、韦氏智能测验数字识记法、数字划消测验分别对患者组进行基线和12周时的测评,同时收集汉族健康对照者178名（对照组）;采用TaqMan等位基因分型方法对2组CYP2D6基因的5个多态性位点（rs1065852、rs1135840、rs 16947、rs1080985、rs5030655）进行基因分型,并对不同多态性位点间患者基线时及治疗12周前后量表得分差值进行比较分析.SHEsis在线软件检测Hardy-Weinberg平衡、成对多态位点连锁不平衡、基因型和等位基因频率分析、单倍型分析比较.结果 rs5030655位点为纯合子,非多态性位点.患者组与对照组在4个多态性位点的基因型分布和等位基因频率差异均无统计学意义（x2=0.439～2.327,均P＞0.05）.rs16947和rs1080985存在较强的连锁不平衡（r2=0.655）.rs16947/rs1065852/rs1080985组成的单倍型AGG在患者组（14.26）中的比例明显大于对照组（7.07）,差异有统计学意义（x2=8.008,P=0.004）.治疗前,rs1135840基因型CC患者的瑞文标准推理测验得分较基因型CG、GG患者得分少（F=3.205,P＜0.05）,经多重检验后差异仍有统计学意义（P=0.038）.治疗后,rs 1135840基因型CC、CG患者的瑞文标准智力测验得分差值均大于基因型GG患者（F=3.590,P=0.031）,经多重检验后差异仍有统计学意义（P=0.036、0.038）;基因型CC和基因型CG患者的得分差之间差异无统计学意义.治疗后,rs 16947基因型AA患者较基因型GG、AG患者的数字划消测验2得分差值小（F=3.249,P=0.043）,经多重检验后差异仍有统计学意义（P=0.022、0.042）,基因型GG和AG患者的得分差值差异无统计学意义.结论 CYP2D6基因多态性与精神分裂症的易感性无关,rs1 135840可能与精神分裂症患者智力损害及治疗后的改善情况相关,rs 16947可能与精神分裂症患者治疗后注意力的改善情况相关.

 Objective To investigate the relationship between the polymorphisms of CYP2D6 gene and clinical efficacy of risperidone in schizophrenia.Methods 114 schizophrenia patients were recruited and completed 12 weeks of treatment with risperidone monotherapy.Positive and Negative Syndrome Scale （PANSS）,Personal and Social Performance Scale （PSP）,Digit Span Test in Wechsler Intelligence Scale,Raven＇s Standard Progressive Matrices,Digital Cancellation Test were used to assess patients psychotic symptoms and cognitive symptom,and all patients were evaluated at baseline and weekend of 12.178 healthy controls were also collected.Five SNPs （rs1065852,rs1135840,rs16947,rs1080985,rs5030655） in CYP2D6 were genotyped by using TaqMan（（R）） SNP Genotyping Assays.SHEsis online software were used to detect the Hardy-Weinberg equilibrium,pairs of polymorphic loci linkage disequilibrium,genotype and allele frequency analysis and haplotype analysis.SPSS17.0 statistical package was used for statistical analysis.Results rs5030655 was found only homozygous,suggesting not polymorphic site.Schizophrenia and control groups were not statistically different in genotype distributions and allele frequencies of four polymorphic sites （P〉0.05）.There was a strong linkage disequilibrium between rs16947 and rs1080985 （r2=0.655）.Haplotype frequency of three SNPs rs16947/rs1065852/rs1080985 AGG in schizophrenia group was significantly greater than in healthy people （14.26 vs.7.07;x2=8.008,P=0.004）.At baseline,CC patients of rs1135840 genotype scored less than CG and GG genotype patients in Raven＇s Standard Progressive Matrices （F=3.205,P〈0.05）,the results still showed statistical significance after Bonferroni corrections （P=0.038）.After the treatment of 12 weeks,CC and CG patients of rs1135840 genotype had greater score changes in Raven＇s Standard Progressive Matrices than patients of the GG genotype （F=3.590,P=0.031）,the results still showed statistical significance after Bonferroni corrections （P=0.036,0.038）,but there was no significant difference between the scores of genotype CC and genotype CG patients （P〉0.05）.After treatment,AA patients of rs16947 genotype had smallest score changes in Digital Cancellation Test（F=3.249,P=0.043）,the results still showed statistical significance after Bonferroni corrections （P=0.022,0.042）,and there was no statistical significant difference between the genotype GG and AG （P〉0.05）.Conclusions There is no relationship between the polymorphism of CYP2D6 gene and the susceptibility of schizophrenia,but rs1135840 may be associated with intellectual impairment at baseline and improvement after treatment in patients with schizophrenia.rs16947 may be associated with improved attention in the treatment of schizophrenia.