Gene Markers: Antipsychotic-Induced Metabolic Syndrome

描述（由申请人提供）：该I期SBIR项目将开发基因诊断产品，以提高非典型抗精神病药物（例如奥氮平）治疗精神疾病（包括精神分裂症）的安全性。非典型抗精神病药物作为长期治疗的处方越来越多的适应症，甚至青少年的患者。在高达50%的患者中，这些高效药物会诱发代谢综合征。哈特福德的Genomas和生活研究所（IOL）汇集了基因组学和专家精神病护理的力量，以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管理。这些新的和高度预测性的标记物被称为“生理型”，并且由各种贡献基因和基线特征的组合产生。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例患者被要求参加本研究，并要求其同意进行遗传分析。患者将接受6个月的随访。将在基线、奥氮平治疗开始后2个月和6个月确定临床评估，包括体重、腰围、血脂、空腹血糖和血压。用高度多重的基因分型分析，基因组将对每个患者的200个基因进行单倍型分析。候选基因来自CNS、代谢、细胞生物学和遗传学研究，代表抗精神病药理学（多巴胺、血清素、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）。基于对医疗记录的回顾，该研究已经能够检测出即使是中等个体预测能力的常见单倍型（优势比为1.7）。当组合成生理型时，标记物具有80%或更高的特异性和灵敏度。基因组将构建药物诱导的代谢综合征的生理型，并将统计验证技术应用于这些发现。生理型产生了关于抗精神病药物药理学和代谢综合征病理生理学的新知识，并成为多基因诊断产品开发的知识产权。生理型将用于个性化治疗、药物监测和医疗预防。这种新的方法利用多生理途径，单倍型，协变量分析和标准化的临床实践将导致个性化的“双预防”诊断自然和药物引起的疾病。

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.