Association of genetic polymorphisms with psychotropic-response in mental disorders

遗传多态性与精神疾病精神治疗反应的关联

• 批准号: 13470198
• 负责人: OZAKI Norio
• 金额: $ 9.22万
• 依托单位: Fujita Health University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470198/
• 关键词: MOOD DISOREDERS; SCHIZOPHRENIA; ANXIETY DISORDERS; GENOME; PHARMACOGENETICS; ANTIPSYCHOTICS; SSRI; 遺伝子; 精神障害; 薬物反応性; 多型

The importance of genetic factors among inter-individual diversities of drug response has been steadily clarified. As a result, pharmacogenetics, which is defined as the science of pharmacological response and its modification by hereditary influence has been extensively carried out in order to clarify a marker of clinical response, put individualized medicine into a reality, and discover a new drug.Thus, we carried out the following pharmacogenetic studies of psychotropics.1.Risperidone response : D2 and 5-HT2A gene haplotype is associated with clinical efficacy of risperidone in schizophrenia.2.SSRI response : Newly identified amino acid substitution in 5-HT transporter gene is associated with treatment resistant familiar obsessive compulsive disorder3.Amphtamine response : VNTR polymorphism of the dopamine transporter gene is a risk factor for methamphetamine induced psychosisWe also elucidated the functional meanings of genetic polymorphism associated with mental disorders or treatment response.1.Pro15Ser in 5-HT5A receptor gene associated with schizophrenia : The expression study using cultured cell revealed that atypical antipsychotics including zotepine, risperidone, clozpine have high affinity to 5-HT5A receptor and the Bmax of the Ser15 is about 50% of that of the Per15.2.Cys23Ser in 5-HT2C receptor gene associated with Clozapine response : The expression study using cultured cell revealed that the Ser23 allele may be constitutively more active than Cys23lWe are going to continue pharmacogenetic studies of psychotropics to obtain a marker for the drug response and open the road to the development of a new drug.

遗传因素在个体间药物反应差异中的重要性已逐渐阐明。因此，药物遗传学（被定义为药理反应及其受遗传影响改变的科学）得到了广泛的开展，以明确临床反应的标志，将个体化医疗变为现实，并发现新药。我们开展了以下精神药物的药代动力学研究。 1.利培酮反应：D2和5-HT2A基因单倍型与利培酮在精神药物中的临床疗效相关。 2.SSRI反应：新发现的5-HT转运蛋白基因中的氨基酸取代与治疗抵抗性熟悉的强迫症有关3.安非他明反应：多巴胺转运蛋白基因的VNTR多态性是甲基苯丙胺诱发精神病的危险因素我们还阐明了功能与精神障碍或治疗反应相关的基因多态性的意义。1.5-HT5A受体中的Pro15Ser与精神分裂症相关的基因：使用培养细胞的表达研究表明，非典型抗精神病药包括佐替平、利培酮、氯氮平对5-HT5A受体具有高亲和力，并且Ser15的Bmax约为5中Per15.2.Cys23Ser的Bmax的50%。 -与氯氮平反应相关的HT2C受体基因：使用培养细胞的表达研究表明Ser23等位基因可能比Cys23l组成性更活跃，我们将继续进行精神药物的药物遗传学研究，以获得药物反应的标志物，为新药的开发开辟道路。

项目成果

Suzuki, T, Ozaki, N et al.: "Association of Novel Genetic Variants in the Serotonin 5-HT4 Receptor Gene (HTR4) with Japanese Schizophrenia"Am J Med Genet. (In press).

Suzuki, T, Ozaki, N 等人：“血清素 5-HT4 受体基因 (HTR4) 中的新型遗传变异与日本精神分裂症的关联”Am J Med Genet。

Yamanouchi, Y, Ozaki, N et al.: "Effects of DRD2, 5-HT2A, and COMT Genes on Risperidone Treatment Response"The Pharmacogenomics Journal. (In press).

Yamanouchi, Y, Ozaki, N 等人：“DRD2、5-HT2A 和 COMT 基因对利培酮治疗反应的影响”药物基因组学杂志。

Okada M, et al.: "Pepstatin A induces extracellular acidification distinct from aspartic protease inhibition in microglial cell line."Glia. 43(2). 167-174 (2003)

Okada M 等人：“胃酶抑素 A 诱导细胞外酸化，与小胶质细胞系中的天冬氨酸蛋白酶抑制不同。”

Ozaki N(分担執筆): "Psychophamacogenetics, in ENCYCLOPEDIA OF THE HUMAN GENOME, vol 4"Macmillan Publishers Ltd, Nature Publishing Group. 917-922 (2003)

Ozaki N（贡献者）：“Psychophamacogenics，in ENCYCLOPEDIA OF THE HUMAN GENOME，第 4 卷”Macmillan Publishers Ltd，自然出版集团 917-922 (2003)。

Hirano S, Sato T, Narita T, Kusunoki K, Ozaki N, Kimura S, Takahashi T, Sakado K, Uehara T: "Evaluating the state dependency of the Temperament and Character Inventory dimensions in patients with major depression: a methodological contribution."J Affect D

Hirano S、Sato T、Narita T、Kusunoki K、Ozaki N、Kimura S、Takahashi T、Sakado K、Uehara T：“评估重度抑郁症患者气质和性格量表维度的状态依赖性：方法论贡献。”