Lithium Effects on Tetrahydrobiopterin Deficit in GHC1-Associated Bipolar Disorde

描述(申请人提供)：四氢生物蝶呤(BH4)是一种重要的辅因子，可维持多巴胺和5-羟色胺等胺类神经递质的可获得性，调节一氧化氮的合成，并刺激和调节谷氨酸能系统。NT系统调节失调与包括双相情感障碍(BPD)在内的精神障碍的发病机制有关。BPD具有很大的遗传成分，对BPD的应用具有重要意义的GCH1基因(编码BH4生物合成途径中的第一个限速酶GTPCH)最近被发现与BPD有关。我们观察到，与对照组相比，患有精神障碍(包括BPD)的患者血浆总生物蝶呤(BH4)缺乏，这种缺陷似乎可以通过锂(Li)治疗得到缓解。这一发现，以及a)BH4在NT维持中的已知作用，以及b)BH4生物合成基因GCH1与BPD的关联，支持了我们的假设，即我们测量的血浆生物蝶呤缺乏与BPD的病因学有关。此外，动物研究数据显示，通过LI上调GCH1 mRNA，支持我们的发现，LI治疗增加了生物蝶呤水平。基于BH4在NT合成中的中心作用，我们现在假设BPD的易感性受到GCH1基因变体的影响，GCH1基因变体降低GCH1 mRNA水平，导致BH4缺陷，LI可以缓解这种缺陷。这一新的假设将在这项研究中得到验证，它基于惊人的初步数据：在30名BPD受试者和46名对照组中，我们证实GCH1与BPD显著相关(OR，3.2p=0.038)，重要的是，我们还表明，携带BPD相关GCH1等位基因的受试者GCH1mRNA水平较低。此外，对17例BPD患者(9例接受LI治疗，8例未接受LI治疗)的分析表明，a)LI治疗增加了GCH1的表达，b)LI治疗后GCH1 mRNA的升高在没有BPD相关GCH1等位基因的患者中最高，这一发现表明LI治疗可能对具有相关等位基因的患者效果较差。基于这些非常令人兴奋的数据，这项探索性研究旨在检验我们的假设，即BPD患者存在血浆BH4缺陷(反映中枢神经系统缺陷)，LI治疗可以缓解这种缺陷，特别是在没有BPD相关GCH1等位基因的患者中。这项研究的具体目的是：1)招募280名BPD受试者，每个人都有与BPD相关的GCH1等位基因，并与280名匹配的对照进行比较。2b)检测治疗前和治疗后外周血中GCH1mRNA的表达；2c)检测治疗前和治疗后血浆中生物蝶呤水平；2d)检测治疗前后BPD患者GCH1基因、GCH1mRNA水平和生物蝶呤之间的相互作用，并检验与评定量表的相关性。了解GCH1和BH4在BPD病因学中的作用可能会改善患者的治疗和临床结果，并对那些有可能发展这种毁灭性疾病的人进行早期干预。

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.