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: 8139260
• 负责人: John R. Kelsoe
• 金额: $ 118.8万
• 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/8139260
• 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，个体之间对此类药物的反应差异很大，通常会导致药物优化的漫长试错过程可能持续数年。非常需要更好的反应预测器，以指导医生以更有效的方式找到最佳药物。遗传差异可能解释了这种变异的很大一部分。该项目的目标是识别与情绪稳定剂药物反应相关的遗传变异，这些变异最终可能可用作预测测试。我们小组迄今为止的研究表明 NTRK2 和 PDE11A 这两个基因可以预测对锂的反应。在这个项目中，我们提出了一种双管齐下的方法：首先在较大的回顾性样本中以探索性方式寻找基因，然后在较小的前瞻性样本中测试其复制情况。在回顾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，但可以提供更好、更定量的数据。我们的 11 个站点联盟最近完成了对 4,500 多名双相情感障碍受试者的收集，以进行大型基因研究。通过重新接触这些先前病例和招募新的回顾性病例，将收集 2,000 名回顾性受试者。 960 名受试者的前瞻性样本将通过八中心多中心试验收集。患者将被招募、筛选并首先在 3 个月的时间内通过锂单药疗法稳定病情。观察1个月后，进入维持阶段，跟踪2年。主要结果指标是复发时间。锂盐失败的患者将换用丙戊酸，两种药物均失败的患者将像往常一样进入治疗组。将对回顾性样本和前瞻性样本中复制的阳性 SNP 进行全基因组关联。二次分析将包括前瞻性样本的全基因组关联以及与回顾性样本的荟萃分析。这些分析将部分以锂在神经元细胞中的作用机制为指导，这些神经元细胞源自诱导多能干细胞，而神经元细胞又源自锂反应者和非反应者的皮肤成纤维细胞。相关性（参见说明）：这个多地点合作项目旨在识别双相情感障碍患者的基因变异，这些变异可以预测对锂的反应。我们将结合对 1600 名 BP 疾病患者的锂反应回顾性评估和基因型数据分析，以及对 1000 名开始使用锂进行公开试验的 BP 患者进行前瞻性研究来实现这一目标。我们的假设是，几个位点的遗传变异可以预测锂的治疗结果。