Roman Tatiana, Rohde Luis Augusto, Hutz Mara Helena
Department of Morphological Sciences, Federal School of Medical Sciences of Porto Alegre, Porto Alegre, Brazil.
Am J Pharmacogenomics. 2004;4(2):83-92. doi: 10.2165/00129785-200404020-00003.
Attention deficit-hyperactivity disorder (ADHD) is a very common and heterogeneous childhood-onset psychiatric disorder, affecting between 3% and 5% of school age children worldwide. Although the neurobiology of ADHD is not completely understood, imbalances in both dopaminergic and noradrenergic systems have been implicated in the origin and persistence of core symptoms, which include inattention, hyperactivity, and impulsivity. The role of a genetic component in its etiology is strongly supported by genetic studies, and several investigations have suggested that the dopamine transporter gene (DAT1; SLC6A3 locus) may be a small-effect susceptibility gene for ADHD. Stimulant medication has a well-documented efficacy in reducing ADHD symptoms. Methylphenidate, the most prescribed stimulant, seems to act mainly by inhibiting the dopamine transporter protein and dopamine reuptake. In fact, its effect is probably related to an increase in extracellular levels of dopamine, especially in brain regions enriched in this protein (i.e. striatum). It is also important to note that dopamine transporter densities seem to be particularly elevated in the brain of ADHD patients, decreasing after treatment with methylphenidate. Altogether, these observations suggest that the dopamine transporter does play a major role in ADHD. Among the several polymorphisms already described in the SLC6A3 locus, a 40 bp variable number of tandem repeats (VNTR) polymorphism has been extensively investigated in association studies with ADHD. Although there are some negative results, the findings from these reports indicate the allele with ten copies of the 40 bp sequence (10-repeat allele) as the risk allele for ADHD. Some investigations have suggested that this polymorphism can be implicated in dopamine transporter gene expression in vitro and dopamine transporter density in vivo, even though it is located in a non-coding region of the SLC6A3 locus. Despite all these data, few studies have addressed the relationship between genetic markers (specifically the VNTR) at the SLC6A3 locus and response to methylphenidate in ADHD patients. A significant effect of the 40 bp VNTR on response to methylphenidate has been detected in most of these reports. However, the findings are inconsistent regarding both the allele (or genotype) involved and the direction of this influence (better or worse response). Thus, further investigations are required to determine if genetic variation due to the VNTR in the dopamine transporter gene is able to predict different levels of clinical response and palatability to methylphenidate in patients with ADHD, and how this information would be useful in clinical practice.
注意缺陷多动障碍（ADHD）是一种非常常见且具有异质性的儿童期起病的精神障碍，全球范围内3%至5%的学龄儿童受其影响。尽管ADHD的神经生物学机制尚未完全明确，但多巴胺能系统和去甲肾上腺素能系统的失衡均与核心症状（包括注意力不集中、多动和冲动）的产生及持续存在有关。遗传学研究有力支持了遗传因素在其病因中的作用，多项调查表明多巴胺转运体基因（DAT1；SLC6A3基因座）可能是ADHD的一个低效应易感基因。兴奋剂药物在减轻ADHD症状方面有充分的疗效记录。最常处方的兴奋剂哌甲酯似乎主要通过抑制多巴胺转运体蛋白和多巴胺再摄取发挥作用。事实上，其作用可能与细胞外多巴胺水平升高有关，尤其是在富含该蛋白的脑区（即纹状体）。还需注意的是，ADHD患者大脑中的多巴胺转运体密度似乎特别升高，在接受哌甲酯治疗后会降低。总之，这些观察结果表明多巴胺转运体在ADHD中确实起主要作用。在SLC6A3基因座已描述的几种多态性中，一种40bp可变串联重复序列（VNTR）多态性在与ADHD的关联研究中得到了广泛研究。尽管有一些阴性结果，但这些报告的发现表明具有10个40bp序列拷贝的等位基因（10重复等位基因）是ADHD的风险等位基因。一些研究表明，这种多态性可能在体外与多巴胺转运体基因表达以及体内与多巴胺转运体密度有关，尽管它位于SLC6A3基因座的非编码区。尽管有所有这些数据，但很少有研究探讨SLC6A3基因座的遗传标记（特别是VNTR）与ADHD患者对哌甲酯反应之间的关系。在大多数这些报告中都检测到了40bp VNTR对哌甲酯反应的显著影响。然而，关于所涉及的等位基因（或基因型）以及这种影响的方向（更好或更差的反应），研究结果并不一致。因此，需要进一步研究以确定多巴胺转运体基因中VNTR导致的基因变异是否能够预测ADHD患者对哌甲酯的不同临床反应水平和耐受性，以及这些信息在临床实践中如何有用。
