Kereszturi Eva, Tarnok Zsanett, Bognar Emese, Lakatos Krisztina, Farkas Luca, Gadoros Julia, Sasvari-Szekely Maria, Nemoda Zsofia
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1431-5. doi: 10.1002/ajmg.b.30704.
Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drug-response is increasingly important. Here we present a case-control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case-control and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecol-O-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele was more frequent in the ADHD group (n = 173) compared to the healthy population (P = 0.016). The categorical analysis of 90 responders versus 32 non-responders showed an association between the Val-allele or Val/Val genotype and good methylphenidate response (P = 0.009 and P = 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity-Impulsivity scale (P = 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P = 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action.
哌甲酯是治疗注意力缺陷多动障碍（ADHD）时最常处方的药物，但并非对所有病例都有效。因此，识别预测药物反应的遗传和/或生物学标志物变得越来越重要。在此，我们展示了一项针对ADHD的病例对照研究以及药物遗传学关联分析，该分析调查了三种多巴胺能多态性。先前的研究表明，多巴胺D4受体（DRD4）和多巴胺转运体（DAT1）基因中的可变串联重复序列（VNTR）是ADHD的遗传风险因素，也是哌甲酯反应的可能标志物。然而，我们的结果并未表明这两个VNTR在ADHD中起重要作用，不过，病例对照分析和药物遗传学分析均显示，儿茶酚-O-甲基转移酶（COMT）Val158Met多态性的高活性Val等位基因在我们的ADHD人群中发挥了重要作用。与健康人群相比，ADHD组（n = 173）中Val等位基因更为常见（P = 0.016）。对90名反应者与32名无反应者进行的分类分析表明，Val等位基因或Val/Val基因型与良好的哌甲酯反应之间存在关联（分别为P = 0.009和P = 0.034）。将症状严重程度作为连续性状进行分析时，发现COMT基因型与哌甲酯在多动冲动量表上存在显著交互作用（P = 0.044）。所有三个基因型组的症状严重程度评分在服用哌甲酯后均有所下降（P < 0.001），然而，治疗后Val/Val纯合子儿童的症状严重程度明显低于Met/Met基因型儿童（P = 0.015）。这种交互作用可能反映了以COMT为主导的前额叶多巴胺传递对皮层下多巴胺系统的调节作用，而皮层下多巴胺系统正是哌甲酯的实际作用部位。
