Lithium Effects on Tetrahydrobiopterin Deficit in GHC1-Associated Bipolar Disorde

描述（由申请人提供）：四氢生物蝶呤（BH 4）是一种重要的辅因子，可维持多巴胺和5-羟色胺等胺神经递质（NT）的可用性，调节一氧化氮合成，刺激和调节谷氨酸能系统。NT系统的失调与包括双相情感障碍（BPD）在内的精神疾病的发病机制有关。BPD具有很大的遗传成分，并且对该应用具有重要意义，GCH 1基因（其编码BH 4生物合成途径中的第一个和限速酶GTPCH）最近与BPD相关。我们已经观察到，与对照受试者相比，患有精神障碍（包括BPD）的患者具有血浆总生物蝶呤（BH 4的量度）的缺乏，这似乎通过锂（Li）治疗而减轻。这一发现，沿着a）BH 4在NT维持中的已知作用，和B）BH 4生物合成基因GCH 1与BPD的关联，支持我们的假设，即我们测量的血浆生物蝶呤缺乏涉及BPD的病因学。此外，显示通过Li上调GCH 1 mRNA的动物研究数据支持我们的发现，Li处理增加生物蝶呤水平。基于BH 4在NT合成中的核心作用，我们现在假设BPD易感性受到GCH 1基因变体的影响，该基因变体降低GCH 1 mRNA水平，导致BH 4缺陷，可以通过Li缓解。这一新的假设将在本研究中得到验证，它是基于惊人的初步数据：在30名BPD受试者和46名对照者中，我们证实GCH 1与BPD显著相关（OR，3.2，p =0.038），重要的是，我们还表明，具有BPD相关GCH 1等位基因的受试者具有较低的GCH 1 mRNA。此外，对17名BPD受试者（9名Li治疗，8名未接受Li治疗）的分析显示，a）Li增加GCH 1表达，和B）Li治疗GCH 1 mRNA的升高在没有BPD相关GCH 1等位基因的患者中最高，这一发现表明Li治疗在具有相关等位基因的患者中可能不太有效。基于这些非常令人兴奋的数据，本探索性研究旨在检验我们的假设，即BPD受试者具有血浆BH 4缺陷（反映CNS缺陷），可以通过Li治疗缓解，特别是在没有BPD相关GCH 1等位基因的患者中。本研究的具体目的是：1）招募280名BPD受试者，对先前与BPD相关的GCH 1等位基因进行基因分型，并与280名匹配对照的基因型进行比较。2a）从根据目标1招募的280名BPD受试者收集Li治疗前和治疗后的血液。2b）测定治疗前和治疗后样品中的外周GCH 1 mRNA表达，2c）测定治疗前和治疗后样品中收集的血浆生物蝶呤水平，和2d）测试Li治疗前和治疗后BPD受试者中GCH 1基因型、GCH 1 mRNA水平和生物蝶呤之间的相互作用，并测试与评估量表的相关性。了解GCH 1和BH 4在BPD病因中的作用可能有助于改善患者的治疗和临床结局，并为那些有发展这种毁灭性疾病风险的人提供早期干预。

DESCRIPTION (provided by applicant): Tetrahydrobiopterin (BH4) is a vital cofactor that maintains availability of amine neurotransmitters (NT) such as Dopamine and Serotonin, regulates Nitric Oxide synthesis, and stimulates and modulates the Glutamatergic system. Dysregulation of NT systems has been implicated in the pathogenesis of psychiatric disorders, including bipolar disorder (BPD). BPD has a large genetic component, and of great significance to this application, the GCH1 gene (which encodes GTPCH, the first and rate-limiting enzyme in the BH4 biosynthesis pathway), was recently associated with BPD. We have observed that patients with psychiatric disorders (including BPD) have a deficit of plasma total biopterin (a measure of BH4) compared to control subjects, that appears to be alleviated via lithium (Li) treatment. This finding, along with a) the known roles of BH4 in NT maintenance, and b) the association of the BH4 biosynthesis gene GCH1 with BPD, supports our hypothesis that our measured plasma biopterin deficit is involved in the etiology of BPD. Furthermore, animal study data showing upregulation of GCH1 mRNA via Li, supports our finding that Li treatment increases biopterin levels. Based on the central roles of BH4 in NT synthesis, we now hypothesize that BPD susceptibility is influenced by a GCH1 gene variant that decreases GCH1 mRNA levels, leading to a BH4 deficit that can be alleviated by Li. This new hypothesis, which will be tested during this study, is based on striking preliminary data: In 30 BPD subjects and 46 controls, we confirmed that GCH1 is significantly associated with BPD (OR, 3.2,p=0.038), and importantly, we also showed that subjects with the BPD-associated GCH1 allele have lower GCH1 mRNA. In addition, analysis of 17 BPD subjects (9 Li treated and 8 not Li treated), showed that a) Li increases GCH1 expression, and b) that Li treatment elevation of GCH1 mRNA is highest in patients without the BPD-associated GCH1 allele, a finding which suggests Li treatment may be less effective in patients with the associated allele. Based on these very exciting data, this exploratory study is designed to test our hypothesis that BPD subjects have a plasma BH4 deficit (reflecting a CNS deficit) that can be alleviated by Li treatment, particularly in patients without the BPD- associated GCH1 allele. The Specific Aims of this study are:1) To recruit 280 BPD subjects, genotype each for the GCH1 allele previously associated with BPD, and compare to genotypes of 280 matched controls. 2a) To collect pre- and post-Li treatment bloods from the 280 BPD subjects recruited under Aim 1. 2b) To Assay peripheral GCH1 mRNA expression in the pre and post-treatment samples 2c) Assay plasma biopterin levels in the collected in the pre and post samples, and 2d) To test for interactions between GCH1 genotype, GCH1 mRNA levels, and biopterin in pre- and post-Li treated BPD subjects and test for correlations with assessment scales. Understanding the roles of GCH1 and BH4 in BPD etiology may allow improved treatment and clinical outcomes for patients, and early interventions for those at risk of developing this devastating illness.