DA/NE核心转化酶DBH在首发精神分裂症发病、临床症状、认知障碍和药物疗效中的作用

Dopamine beta-hydroxylase (DBH) is a key enzyme, which converts dopamine (DA) to norepinephrine (NE). DA and NE in schizophrenia have been reported: association with the pathogenesis, clinical phenotype (clinical symptoms, and cognitive impairments) and antipsychotic efficacy. Our previous studies showed that DBH rs141116007 polymorphism was association with schizophrenic (SCH) development, and clinical phenotype, which have been published in the journals: Journal of Clinical Psychiatry, Journal of Psychiatric Research and Schizophrenia Research. However, the analyses for the roles of DBH genotypes, DBH regulations, DBH expressions, and DBH transcription in the pathogenesis, clinical phenotype and antipsychotic efficacy still weren’t reported in first-episode schizophrenia (FES). Therefore, we provided a hypothesis: DA/NE key converting enzyme DBH was involved in FES pathogenesis, clinical phenotype and antipsychotic efficacy. 300 FES are randomly assigned to 8 weeks of treatment with antipsychotic drugs. Also, 300 healthy controls will be recruited as comparison. DBH and its related-miRNAs genotypes in all subjects will be tested by TaqMan Single Nucleotide Polymorphism (SNP) Genotyping Assay. DBH related-miRNAs and mRNA expressions, and DBH levels and activities will be tested by reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and high performance liquid chromatography (HPLC) in 300 FES before and after treatment, and 300 healthy controls. We will clarify the role of DA/NE key converting enzyme DBH in FES pathogenesis, clinical phenotype and antipsychotic efficacy, which will further provide scientific basis for finding SCH diagnosis and treatment targets.

多巴胺β羟化酶（DBH）是多巴胺（DA）和去甲肾上腺素（NE）的核心转化酶，DA和NE参与了精神分裂症（SCH）发病、临床表型和药物疗效。我们前期发现DBH rs141116007与SCH发病和临床表型有关，其结果已发表: Journal of Clinical Psychiatry，Journal of Psychiatric Research 和Schizophrenia Research，但从“基因型→基因调控→基因表达→基因转录”探讨DBH在首发精神分裂症（FES）发病、临床表型和药物疗效中的作用，尚未见报道。因此，我们提出：DBH参与了FES发病、临床表型和药物疗效。本研究入组300例FES采用自然给药8周，300例健康人做对照，利用TaqMan、RT-PCR、ELISA和HPLC方法检测DBH，并阐明其在FES发病、临床表型和药物疗效中的作用，为寻找SCH诊疗靶点提供科学依据。

DBH是DA和NE的核心转化酶，DA和NE参与了SCH发病、临床表型和药物疗效。前期发现DBH 与SCH有关，但系统探讨DBH在FES发病、临床表型和药物疗效中的作用，尚未见报道。因此，我们提出：DBH参与了FES发病、临床表型和药物疗效。本研究入组593例FES，767例CSP，748例HCs，评估了精神症状和认知，通过ELISA和TaqMAN技术检测DBH SNPs和蛋白水平及其它生物学指标。也入组了MDD和BP患者，检测了生物标记物。DBH单倍型、DBH SNP和PLA2G12A分型、ALB和TBIL在FES和HCs间存在差异。DBH分型影响FES DBH水平及药物疗效，DBH、PLA2G12A、CDKAL1、COX-2、DRD2、IL-18分型变化、DBH、ALB和TBIL水平变化与SCH临床表型相关。相比HCs，FES和CSP组均存在认知和立体视觉损伤。MDD组IL-6水平高于HCs，IL-6水平与患者持续注意呈正相关，女性高TG MDD组出现认知下降，性激素降低影响女性高TG MDD发生及认知下降，ApoB与患者即刻记忆呈负相关。DCC基因是MDD易感基因。HDL水平影响BP发生及认知功能。GWAS发现：TMEM108, VRK2和RHEBL1为BP易感基因。这些结果建议：DBH调控DBH水平进而影响SCH发病、临床表型和药物疗效；PLA2G12A，CDKAL1,COX-2,DRD2,IL-18分型及ALB和TBIL水平涉及SCH发病和临床表型。DCC分型、IL-6和ApoB水平涉及MDD发病和临床表型。在MDD中TG,性激素，性别和认知之间存在关系；HDL水平及TMEM108等基因分型影响BP发病及认知功能。.上述成果总结并发表论文28篇，SCI收录15篇，项目负责人第一/通讯作者SCI收录14篇（并列），中华杂志2篇，该课题成果将为精神疾病诊疗提供了理论依据。