Gene Markers: Antipsychotic-Induced Metabolic Syndrome

描述(由申请人提供)：该第一阶段SBIR计划将开发基因诊断产品，以提高非典型抗精神病药物(如奥氮平)治疗精神障碍(包括精神分裂症)的安全性。对于越来越多的适应症，非典型抗精神病药物被作为长期治疗药物，甚至对青少年患者也是如此。在高达50%的患者中，这些高效药物会导致代谢综合征。Genoma和位于哈特福德的生活研究所(IOL)将基因组学和专家精神护理的力量结合在一起，发现药物诱导的代谢综合征易感性的遗传标记，用于精神疾病的临床治疗。这些新的和高预测性的标记被称为“生理型”，是各种贡献基因和基线特征组合的结果。作为IOL最佳医疗实践的一部分，首次接受奥氮平治疗的患者中，将有250人被要求参加这项研究，并要求同意进行基因分析。对患者进行为期6个月的随访。临床评估，包括体重、腰围、血脂、空腹血糖和血压将在基线以及奥氮平开始治疗2个月和6个月后确定。Genoma将通过高度多元化的基因分型分析，对每个患者的200个基因进行单倍型分析。候选基因来自中枢神经系统、代谢、细胞生物学和遗传学研究，代表抗精神病药物(多巴胺、5-羟色胺、组胺)、食欲控制(瘦素、神经肽Y)、能量调节(解偶联蛋白)、内分泌学(胰岛素)和胆固醇稳态(载脂蛋白)。基于对医疗记录的审查，这项研究被用来检测常见的单倍型，即使是适度的个体预测能力(优势比为1.7)。当结合成生理类型时，这些标记具有80%或更高的特异性和敏感性。Genoma将构建药物诱导的代谢综合征的生理类型，并将统计验证技术应用于这些发现。生理学产生了关于代谢综合征的抗精神病药物药理学和病理生理学的新知识，并成为开发多基因诊断产品的知识产权。生理型将在个性化治疗、药物监测和医学预防中发挥作用。这一新的方法利用多个生理通路、单倍型、协变量分析和标准化的临床实践，将导致对自然疾病和药物引起的疾病进行个性化的“双预防”诊断。

DESCRIPTION (PROVIDED BY APPLICANT): This Phase I SBIR Program will develop genetic diagnostic products to improve the safety of atypical antipsychotics (e.g. olanzapine) for treating psychiatric disorders, including schizophrenia. Atypical antipsychotics are prescribed as long-term treatments for an increasing number of indications even to adolescent's patients. In up to 50% of patients, these highly effective drugs induce metabolic syndrome. Genomas and the Institute of Living (IOL) at Hartford bring together the power of genomics and expert psychiatric care to discover genetic markers of susceptibility to drug-induced metabolic syndrome for clinical management of psychiatric disorders. These novel and highly predictive markers are termed "physiotypes" and result from combinations of various contributory genes and baseline characteristics. From patients being first treated with olanzapine as part of best medical practices at IOL, 250 will be asked to participate in this study and requested to consent for genetic analysis. Patients will be followed for 6 months. Clinical assessment, including weight, waist size, lipids, fasting blood glucose and blood pressure will be ascertained at baseline, and 2 and 6 months after initiation of olanzapine treatment. Genomas will haplotype 200 genes in each patient with highly multiplexed genotyping assays. Candidate genes are drawn from CNS, metabolic, cell biological, and genetic studies and represent antipsychotic pharmacology (dopamine, serotonin, histamine), appetite control (leptin, neuropeptide Y), energy regulation (uncoupling proteins), endocrinology (insulin) and cholesterol homeostasis (apolipoproteins). Based on review of medical records, the study has been powered to detect common haplotypes of even modest individual predictive power (odds ratio of 1.7). When combined into physiotypes, the markers have specificity and sensitivity of 80% or more. Genomas will construct physiotypes of drug-induced metabolic syndrome and apply statistical validation techniques to the discoveries. The physiotype generates new knowledge about antipsychotic pharmacology and pathophysiology of metabolic syndrome and becomes intellectual property for development of multigene diagnostic products. The physiotype will have utility for personalized therapy, drug monitoring, and medical prophylaxis. This novel approach utilizing multple physiological pathways, haplotyping, covariate analysis and standardized clinical practice will result in personalized "double-preventive" diagnostics of natural and drug-induced disease.