Short Allele of 5-HTTLPR as a Risk Factor for the Development of Psychosis in Japanese Methamphetamine Abusers
Short Allele of 5-HTTLPR as a Risk Factor for the Development of Psychosis in Japanese Methamphetamine Abusers
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DOI：
10.1196/annals.1432.011
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Mori, Norio
中科院分区：
文献类型：
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作者：
Ezaki, Norikazu;Nakamura, Kazuhiko;Mori, Norio
越来越多的证据表明，遗传因素导致易受甲基苯丙胺(MAP)滥用和相关精神症状的影响。长期滥用MAP会导致精神病，可能是暂时性的，也可能是长期性的。5-羟色胺能功能障碍被认为是MAP精神病发生的重要因素之一。我们的PET研究显示，在MAP滥用者中，全球脑区的5-HTT密度明显较低。在这项研究中，我们研究了5-HTT基因5‘侧翼区的功能多态(5-HTTLPR)在日本人群MAP精神病发生中的作用。我们分析了166名MAP患者(95名一过性精神病患者和71名长期精神病患者)和197名年龄、性别和地理来源匹配的健康对照组的DNA样本。根据有无自发复发将患者细分为119例和148例。我们观察到5-HTTLPR基因多态与MAP精神病显著相关(P=0.022)，特别是在表现为长期精神病的患者中。S等位基因频率在迁延性精神病患者显著高于对照组(P=0.045)，在迁延性精神病自然复发患者中更高(P=0.004)。5-HTTLPR被认为可以调节5-HTT的转录活性，S等位基因的转录效率较低，5-HT1a受体结合潜力也较低。长期使用MAP，结合高频率的5-HTTLPR S等位基因，可能导致脑内5-HTT水平和5-HT1a受体结合电位降低，导致5-羟色胺能系统功能障碍。因此，我们认为5-HTTLPR基因多态性在MAP精神病中可能起作用。
Accumulating evidence suggests that genetic factors contribute to the vulnerability to methamphetamine (MAP) abuse and associated psychiatric symptoms. Chronic MAP abuse leads to psychosis, which may be of a transient or a prolonged type. Serotonergic dysfunction has been proposed as one of the contributory factors in the development of MAP psychosis. Our PET studies revealed that the serotonin transporter (5-HTT) density in global brain regions is significantly lower in MAP abusers. In this study, we examined the role of a functional polymorphism in the 5' flanking region of the 5-HTT gene (5-HTTLPR) in the development of MAP psychosis in a Japanese population. We analyzed DNA samples from 166 MAP patients (95 with transient and 71 with prolonged psychosis) and 197 age-, sex-, and geographic-origin-matched healthy controls. Patients were also subdivided according to the presence (n = 119) or absence (n = 148) of spontaneous relapse. We observed significant genotypic association of the 5-HTTLPR polymorphism with MAP psychosis (P = 0.022), particularly in patients who show prolonged psychosis. The frequency of the S allele in patients with prolonged psychosis was significantly higher than that of the controls (P = 0.045); it was further higher in patients with prolonged psychosis with spontaneous relapse (P = 0.004). 5-HTTLPR has been suggested to regulate the transcriptional activity of 5-HTT, with S alleles showing lesser transcriptional efficiency and also lower 5-HT1A receptor-binding potential. Prolonged MAP use, combined with the high frequency of 5-HTTLPR S-alleles, may lead to reduced 5-HTT levels and 5-HT1A receptor-binding potential in the brain, resulting in the dysfunction of the serotonergic system. Thus, we suggest a possible role for the 5-HTTLPR polymorphism in MAP psychosis.