A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder.
A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder.
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DOI：
10.1097/chi.0b013e3181bc72e3
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发表时间：
2009-12
影响因子：
13.3
通讯作者：
Sugar CA
中科院分区：
文献类型：
--
作者：
McGough JJ;McCracken JT;Loo SK;Manganiello M;Leung MC;Tietjens JR;Trinh T;Baweja S;Suddath R;Smalley SL;Hellemann G;Sugar CA
这项研究考察了候选基因在调节哌醋甲酯(MPH)在注意缺陷/多动障碍(ADHD)治疗效果中的潜在作用。82名6至17岁的ADHD受试者参加了一项前瞻性、双盲、安慰剂对照、多剂量交叉滴定试验，每天三次。受试者接受了各种家长和临床医生的评估，以及实验室的数学测试。基于主成分分析的数据缩减确定了统计得出的疗效和副作用结果。ADHD症状反应通过5-羟色胺转运体(SLC6A4)内含子2 VNTR的多态来预测(p=0.01)，儿茶酚-O-甲基转移酶(COMT)的多态趋势(p=0.04)。在数学测试结果中，在多巴胺D4受体(DRD4)启动子(p=0.008)、DRD4外显子3 VNTR(p=0.006)和SLC6A4启动子插入/缺失多态(5HTTLPR)(p=0.02)的数学测试结果中注意到了基因×剂量的交互作用。应激性由COMT预测(p=0.02)。5HTTLPR可预测植物症状(p=0.003)。多巴胺转运体(SLC6A3)或突触体相关蛋白25(SNAP25)没有显著影响。这份报告证实并扩展了先前的研究，即基因对ADHD的治疗反应是适度的。ADHD的结果不是单一的，但反映了可能受不同基因影响的行为和学习领域。未来的研究应该强调在更大的样本中进行候选基因和基因组范围的关联研究，症状的减轻以及副作用的结果，以及在整个治疗剂量范围内的反应，以评估基因和基因×剂量交互作用的差异。
This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in Attention-Deficit/Hyperactivity Disorder (ADHD). Eighty two subjects with ADHD aged 6 to 17 participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. Subjects were assessed on a variety of parent and clinician ratings, and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes. ADHD symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p=.01), with a suggested trend for catechol-O-methyltransferase (COMT) (p=.04). Gene × dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p=.008), DRD4 exon 3 VNTR (p=.006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p=.02). Irritability was predicted by COMT (p=.02). Vegetative symptoms were predicted by 5HTTLPR (p=.003). No significance effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25). This report confirms and expands previous studies suggesting that genes moderate ADHD treatment response. ADHD outcomes are not unitary, but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene × dose interactive effects.