多巴胺β羟化酶基因变异对注意缺陷多动障碍儿童托莫西汀疗效的影响
Variants of Dopamine Beta Hydroxylase Gene Moderate Atomoxetine Response in Children with Attention-Deficit/Hyperactivity Disorder.
作者信息
Fang Yantong, Ji Ning, Cao Qingjiu, Su Yi, Chen Min, Wang Yufeng, Yang Li
机构信息
1 The Affiliated Hospital Hangzhou Normal University , Hangzhou, China .
2 Beijing University Sixth Hospital/Institute of Mental Health , Key Laboratory of Mental Health, Ministry of Health, Beijing, China .
出版信息
J Child Adolesc Psychopharmacol. 2015 Oct;25(8):625-32. doi: 10.1089/cap.2014.0178. Epub 2015 Oct 8.
OBJECTIVE
Atomoxetine is the most widely used nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). It selectively acts on the norepinephrine (NE) system. Dopamine beta hydroxylase (DBH) regulates the synthesis of NE. This study aimed to investigate whether variants in the DBH gene have an effect on the differential response to atomoxetine.
METHODS
Children and adolescents with ADHD were enrolled in a prospective, open-label study of atomoxetine for 8-12 weeks. The dose was titrated to 1.2-1.4 mg/kg per day and maintained for at least 4 weeks. The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV (ADHD-RS-IV). Three categorical evaluations of treatment effects (defined as response, robust response, and remission) were used. We used a candidate gene approach. Eight single nucleotide polymorphisms (SNPs) in DBH were selected and genotyped based on the functional annotation in literature. Their association with response or remission status was analyzed.
RESULTS
Four SNPs were found nominally associated with response status (rs1076150, p = 0.0484; rs2873804, p = 0.0348; rs1548364, p = 0.0383; and rs2519154, p = 0.0097), two were associated with robust response (rs1076150, p = 0.0349; and rs2519154, p = 0.0047), and one was associated with remission (rs2519154, p = 0.0479). The association between rs2519154 and robust response was significant after correction of multiple comparison (p = 0.0384). Two haplotypes of linkage disequilibrium (LD) block1 (constituted by rs1108580, rs2873804, rs1548364, and rs2519154) were nominally associated with response and robust response status (CTAC: p = 0.0301 for response, p = 0.0374 for robust response; TCGT: p = 0.0317 for response, p = 0.021 for robust response), whereas one haplotype (GC) of LD block2 (constituted by rs2073837 and rs129882) was associated with robust response and remission status (p = 0.0377 for robust response; p = 0.0321 for remission), although none achieved significant threshold after multiple comparison.
CONCLUSIONS
Variants in DBH genes were associated with atomoxetine response in the treatment of ADHD. Further replication in larger samples would be warranted.
目的
托莫西汀是治疗注意力缺陷多动障碍（ADHD）最广泛使用的非兴奋剂。它选择性作用于去甲肾上腺素（NE）系统。多巴胺β羟化酶（DBH）调节NE的合成。本研究旨在调查DBH基因变异是否对托莫西汀的差异反应有影响。
方法
患有ADHD的儿童和青少年参加了一项为期8 - 12周的托莫西汀前瞻性开放标签研究。剂量滴定至每日1.2 - 1.4mg/kg并维持至少4周。主要疗效指标是研究者评定的ADHD评定量表-IV（ADHD-RS-IV）。使用了三种治疗效果的分类评估（定义为反应、强烈反应和缓解）。我们采用候选基因方法。根据文献中的功能注释选择并对DBH中的八个单核苷酸多态性（SNP）进行基因分型。分析它们与反应或缓解状态的关联。
结果
发现四个SNP与反应状态名义上相关（rs1076150，p = 0.0484；rs2873804，p = 0.0348；rs1548364，p = 0.0383；rs2519154，p = 0.0097），两个与强烈反应相关（rs1076应相关（rs1076150，p = 0.0349；rs2519154，p = 0.0047），一个与缓解相关（rs2519154，p = 0.0479）。在进行多重比较校正后，rs2519154与强烈反应之间的关联具有显著性（p = 0.0384）。连锁不平衡（LD）块1的两种单倍型（由rs1108应状态名义上相关（CTAC：反应p = 0.0301，强烈反应p = 0.0374；TCGT：反应p = 0.0317，强烈反应p = 0.021），而LD块失相关（rs2073837和rs129882构成）的一种单倍型（GC）与强烈反应和缓解状态相关（强烈反应p = 0.0377；缓解p = 0.0321），尽管在多重比较后均未达到显著阈值。
结论
DBH基因变异与托莫西汀治疗ADHD的反应相关。有必要在更大样本中进行进一步验证。
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