欧洲裔巴西精神分裂症患者对典型抗精神病药物治疗抵抗的自然主义药物遗传学研究。
Naturalistic pharmacogenetic study of treatment resistance to typical neuroleptics in European-Brazilian schizophrenics.
作者信息
Kohlrausch Fabiana B, Gama Clarissa S, Lobato Maria Inês, Belmonte-de-Abreu Paulo, Callegari-Jacques Sidia M, Gesteira Alejandro, Barros Francisco, Carracedo Angel, Hutz Mara H
机构信息
Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
出版信息
Pharmacogenet Genomics. 2008 Jul;18(7):599-609. doi: 10.1097/FPC.0b013e328301a763.
OBJECTIVES
This study aimed to explore the influence of variation in DRD2, DRD3, CYP2D6, CYP3A4, and CYP3A5 genes on treatment resistance to typical neuroleptics in a Brazilian sample of patients with schizophrenia.
METHODS
One polymorphism at DRD2 gene, five at DRD3, 24 at CYP2D6, nine at CYP3A4 gene, and one at CYP3A5 gene were genotyped in a sample of 186 patients with schizophrenia.
RESULTS
From the nine studied CYP3A4 single nucleotide polymorphisms, only the -392A>G was polymorphic, and significant associations were observed between this single nucleotide polymorphism and efficacy of neuroleptic treatment. Homozygous individuals for the -392A variant [P=0.014, odds ratio (OR)=3.32] were more frequent in the treatment-resistant group, compared with carriers of one copy of the -392G variant. The CYP3A5 low expressor genotype (CYP3A53/CYP3A53) was found to be associated with refractoriness to neuroleptic treatment (P=0.003, OR=3.16). Among the haplotypes observed in DRD3 gene, the T/A/G/A/C haplotype showed an association with refractoriness to neuroleptics (chi=5.342, P=0.021, OR=1.75). This association showed that carriers of one copy of this haplotype presented intermediate values between noncarriers and homozygous individuals for the haplotype. No association was observed with polymorphisms in DRD2 and CYP2D6 genes. Multiple logistic regression analyses showed that the number of copies of DRD3 T/A/G/A/C haplotype and CYP3A5 low expressor genotype were predictors of refractoriness to neuroleptic after controlling for selected risk factors. CYP3A53 individuals carrying at least one copy of the T/A/G/A/C haplotype showed a higher risk to be refractory to neuroleptics than CYP3A53 homozygotes+non-T/A/G/A/C carriers (chi=5.533, P=0.019, OR=2.32, 95% confidence interval=1.08-5.02). No significant associations were observed with DRD2 and CYP2D6 polymorphisms.
CONCLUSION
Our results suggest a role for CYP3A5 and DRD3 gene variants on refractoriness to neuroleptic treatment in Brazilians with schizophrenia.
目的
本研究旨在探讨DRD2、DRD3、CYP2D6、CYP3A4和CYP3A5基因变异对巴西精神分裂症患者样本中典型抗精神病药物治疗耐药性的影响。
方法
对186例精神分裂症患者样本进行DRD2基因的1个多态性、DRD3基因的5个多态性、CYP2D6基因的24个多态性、CYP3A4基因的9个多态性以及CYP3A5基因的1个多态性的基因分型。
结果
在研究的9个CYP3A4单核苷酸多态性中，只有-392A>G是多态性的，并且观察到该单核苷酸多态性与抗精神病药物治疗疗效之间存在显著关联。与携带一份-392G变异拷贝的个体相比，-392A变异的纯合个体[P=0.014，比值比(OR)=3.32]在治疗耐药组中更为常见。发现CYP3A5低表达基因型(CYP3A53/CYP3A53)与抗精神病药物治疗难治性相关(P=0.003，OR=3.16)。在DRD3基因观察到的单倍型中，T/A/G/A/C单倍型显示与抗精神病药物难治性相关(χ=5.342，P=0.021，OR=1.75)。这种关联表明，该单倍型一份拷贝的携带者在非携带者和该单倍型纯合个体之间呈现中间值。未观察到DRD2和CYP2D6基因多态性之间的关联。多因素logistic回归分析显示，在控制选定的危险因素后，DRD3 T/A/G/A/C单倍型的拷贝数和CYP3A5低表达基因型是抗精神病药物难治性的预测指标。携带至少一份T/A/G/A/C单倍型拷贝的CYP3A53个体比CYP3A53纯合子+非T/A/G/A/C携带者对抗精神病药物难治的风险更高(χ=5.533，P=0.019，OR=2.32，95%置信区间=1.08-5.02)。未观察到与DRD2和CYP2D6多态性的显著关联。
结论
我们的结果表明，CYP3A5和DRD3基因变异在巴西精神分裂症患者抗精神病药物治疗难治性中起作用。
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