Pharmacogenomics of Mood Stabilizer Response in Bipolar Disorder

双相情感障碍情绪稳定剂反应的药物基因组学

• 批准号: 7867605
• 负责人: John R. Kelsoe
• 金额: $ 149.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867605
• 关键词: Biopsy; Bipolar Disorder; Cell Culture Techniques; Cells; Collaborations; Collection; Data; Disease; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Crossing Over; Genomics; Genotype; Goals; Human; In Vitro; Individual; Instruction; Lead; Lithium; Maintenance; Meta-Analysis; Modeling; Molecular Profiling; Mood stabilizers; Multicenter Trials; NTRK2 gene; Neurons; Outcome Measure; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phase; Phenotype; Physicians; Process; Prospective Studies; Recontacts; Recording of previous events; Recruitment Activity; Relapse; Relative (related person); Research Institute; Retrospective Studies; Sampling; Site; Skin; Surveys; Testing; Time; Treatment outcome; Valproic Acid; arm; design; disorder later incidence prevention; genetic variant; genome wide association study; genome-wide; human data; induced pluripotent stem cell; nerve stem cell; phosphodiesterase 11a; primary outcome; prospective; response; treatment as usual

DESCRIPTION (provided by applicant): Mood stabilizer treatment is central to the pharmacological management of patients with bipolar disorder. However, response to such agents is highly variable between individuals often resulting in a lengthy trial and error process of medication optimization that can last years. There is a great need for a better predictor of response which would guide physicians to the optimum medication in a more efficient fashion. Genetic differences likely explain a substantial portion of this variability. The goal of this project is to identify genetic variants that are associated with response to mood stabilizer medications that might ultimately be useful as a predictive test. Studies to date by our group have implicated two genes, NTRK2 and PDE11A as predicting response to lithium. In this project, we propose a two pronged approach: genes will first be sought in an exploratory fashion in a larger retrospective sample and then tested for replication in a smaller prospective sample. Larger samples are more easily obtainable in a retrospective study, however, prospective designs though more difficult, provide better and more quantitative data. Our 11 site consortium has recently completed collection of over 4,500 bipolar subjects for a large genetic study. 2,000 retrospective subjects will be collected from both recontact of these previous cases and recruitment of new retrospective cases. The prospective sample of 960 subjects will be collected through an eight site multicenter trial. Patients will be recruited, screened and stabilized first on lithium monotherapy over a 3 month period. After one month observation, they will enter the maintenance phase and followed for 2 years. The primary outcome measure will be time to relapse. Patients who fail lithium will be crossed over to valproic acid, those failing both drugs will enter the treatment as usual arm. Genomewide association will be performed on the retrospective sample and positive SNPs replicated in the prospective sample. Secondary analyses will include genomewide association ofthe prospective sample alone and in meta-analysis with the retrospective sample. These analyses will be guided in part by studies of lithium's mechanism of action in neuronal cells derived from induced pluripotent stem cells in turn derived from skin fibroblasts from lithium responders and non-responders. RELEVANCE (See instructions): This multi-site collaborative project aims to identify genetic variants in individuals with bipolar disorder that predict response to lithium. We will do this with a combination of retrospective assessment of lithium response in 1600 individuals with BP disorder and analysis of genotype data, as well as a prospective study of 1000 BP individuals who begin an open trial with lithium. Our hypothesis is that genetic variants at several loci predict treatment outcomes with lithium.

描述(由申请人提供)： 情绪稳定剂治疗是双相情感障碍患者药物治疗的核心。然而，对这种药物的反应在不同的人之间是高度不同的，经常导致药物优化的漫长的试验和错误过程，可能持续数年。非常需要一种更好的反应预测指标，以更有效的方式指导医生选择最佳的药物治疗。遗传差异可能解释了这种差异的很大一部分原因。该项目的目标是识别与情绪稳定剂药物反应相关的基因变异，这些变异最终可能作为一种预测性测试有用。到目前为止，我们团队的研究表明，NTRK2和PDE11A这两个基因可以预测锂的反应。在这个项目中，我们提出了一个双管齐下的方法：首先以探索性的方式在更大的追溯样本中寻找基因，然后在较小的预期样本中测试复制。在回溯性研究中更容易获得更大的样本，然而，前瞻性设计虽然更困难，但提供了更好和更定量的数据。我们的11站点联盟最近完成了一项大型基因研究的4500多个双相受试者的收集工作。将从重新接触这些以前的病例和招募新的回顾病例中收集2000名回顾对象。960名受试者的预期样本将通过八个地点的多中心试验收集。患者将在3个月内首先接受锂单一疗法的招募、筛查和稳定。观察一个月后，进入维护阶段，跟踪观察2年。主要的结果衡量标准将是复发时间。锂盐不及格的患者将被交叉使用丙戊酸，两种药物都不及格的患者将像往常一样接受治疗。将对回溯性样本和在预期样本中复制的阳性SNP进行全基因组关联。二次分析将包括未来样本的全基因组关联，以及与回溯样本的荟萃分析。这些分析将在一定程度上受到锂在神经细胞中的作用机制研究的指导，这些神经细胞来自诱导多能干细胞，而诱导多能干细胞又来自锂响应者和无反应者的皮肤成纤维细胞。相关性(见说明)：这个多站点合作项目旨在识别双相情感障碍患者中预测锂反应的遗传变异。我们将结合对1600名患有BP疾病的患者的锂反应的回顾评估和对基因数据的分析，以及对开始使用锂的开放试验的1000名BP个人的前瞻性研究来实现这一点。我们的假设是，几个基因座的遗传变异可以预测锂治疗的结果。