請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48289完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 饒宇東 | |
| dc.contributor.author | Yun-Ru Liu | en |
| dc.contributor.author | 劉韻如 | zh_TW |
| dc.date.accessioned | 2021-06-15T06:51:25Z | - |
| dc.date.available | 2012-03-03 | |
| dc.date.copyright | 2011-03-03 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-02-15 | |
| dc.identifier.citation | (1997). 'Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.' Diabetes Care 20(7): 1183-97.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48289 | - |
| dc.description.abstract | 精神分裂症患者的死亡風險比一般族群高出 2 ~ 3 倍，使得患者的平均壽命也相對縮短，這些過高的死亡率除了來自於自殺及意外事故，另一項主因則是由心血管疾病造成的自然死亡，這些心血管疾病高發生率的原因可能來自於精神分裂症疾病本身的遺傳因子，也可能與生活習慣或抗精神病藥物治療等環境因子相關，像是飲食偏向高脂肪低纖維及缺乏運動等，而造成各種肥胖的表現型，進而促成心血管疾病的發生。本研究探討慢性精神分裂症患者肥胖相關性狀（obesity–related phenotype）與候選基因的關連。我們挑選了 glutamate decarboxylase 65、 67（GAD65 and GAD67）及 adrenergic receptor alpha–1a（ADRA1A）基因進行多型性的偵測，試圖找出基因多型性與精神分裂症患者之肥胖相關性狀的相關性。 GAD65 及 GAD67 為合成抑制性神經傳導物質 — GABA（γ–aminobutyric acid）的重要酵素， GAD65 除了在腦部表現，還存在於胰臟的 β–cell，自體免疫系統產生 GAD65 抗體被認為可破壞 β–cell，與糖尿病的形成有關，並廣泛成為糖尿病病程發展的指標，還可利用於糖尿病分型。 ADRA1A 基因與精神分裂症有關，同時，臨床上抗精神病藥物若伴隨著 adrenergic receptors antagonist 同時治療時，能夠加強精神分裂症病患對藥物的反應。 ADRA1A 為交感神經系統重要的訊息傳遞者之一，可調節基礎代謝率的維持、體溫的恒定及能量的利用。 ADRA1A 可能藉由交感神經系統的調控，影響慢性精神分裂症患者的肥胖相關性狀。本研究徵求401 名慢性精神分裂症患者，對其作長期的觀察，並詳細記錄其肥胖相關性狀，例如 BMI、血糖、血脂肪、胰島素等，與環境變數如抽菸、飲食、運動習慣及抗精神病藥物的用藥紀錄等，且萃取其 DNA，以進行 GAD65、 GAD67 及 ADRA1A 等基因多型性的偵測。線性迴歸分析結果發現 GAD67 僅與患者的 HbA1c 百分比相關， GAD65 則可同時影響 glucose、 HbA1c、 total cholesterol、 triglyceride 及 LDL 的含量，且在男性與女性的表現不同，即便排除糖尿病及抗精神病藥物等變項影響後，相關性仍然存在。而 GAD65 雖然在分析結果中與 insulin 濃度的關係不強，但由於其能同時影響 glucose 及 triglyceride，所以可能與 insulin resistance 的發生有關。 ADRA1A 與患者普遍肥胖的情形有關，以年齡、性別、教育程度、抽菸行為、活動狀況、糖尿病史及抗精神病藥物用藥紀錄等作校正後， ADRA1A 基因仍可影響患者 BMI 的變化，並在不同性別間的作用有所不同。本研究顯示 GAD65、 GAD67 及 ADRA1A 基因對精神分裂症患者普遍出現的肥胖相關性狀有所貢獻，本身也造成影響，未來再回歸至臨床治療面，以期能作到根據藥物基因學作為基礎，針對不同的個體施以不同的治療，避免藥物所引起的副作用，使得治療能得到最佳功效，進而提升精神分裂症患者的生活品質。 | zh_TW |
| dc.description.abstract | The risk of mortality in schizophrenia patients is 2-3 times higher than the general population. As a result, average lifespan of schizophrenia patients is relatively shorter. In addition to suicide and accident, the risk of mortality also comes from the natural death caused by cardiovascular diseases. The cardiovascular diseases may be caused by genetic factors. However, lifestyle, antipsychotics treatment and other environmental factors like high-lipid-low-fiber diet and lack of exercise, may cause a variety of obesity related phenotypes that contribute to the development of cardiovascular diseases. This study explored the associations of candidate genes and obesity related phenotypes in chronic schizophrenia patients. The candidate genes included glutamate decarboxylases-65（GAD65）, glutamate decarboxylase-67（GAD67）and adrenergic receptor | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T06:51:25Z (GMT). No. of bitstreams: 1 ntu-100-D90444002-1.pdf: 9084093 bytes, checksum: 4a2eba0396b55c35970dd4fa7d60eb60 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 口試委員會審定書……………………………………………… Ⅰ
中文摘要………………………………………………………… Ⅱ 英文摘要……………………………………………………… Ⅳ 第一章 序論……………………………………………………….……...…..….. 1. 1.1 Schizophrenia.…………………………………………………...…… 1 1.1.1 Epidemiology………………………………………………..... 1 1.1.2 Etiology…………………………………………………..….... 1 1.1.3 Brain Pathology……………………………………………….. 2 1.1.4 Diagnosis……………………………………………...………. 3 1.1.5 Positive and Negative Syndrome Scale…………………...….. 4 1.1.6 Drug Treatment and Side Effects………………………..……. 4 1.1.7 Schizophrenia and Diabetes……………………………...…… 5 1.1.8 The Metabolic Syndrome in Schizophrenia……………...…… 7 1.1.9 Immunology…………………………………………………... 9 1.1.10 Smoking and Schizophrenia………………………….…….. 12 1.2 GABA…………………………………………………………….… 16 1.2.1 Introduction………………………………………………..… 16 1.2.2 Related Disease……………………………………………… 17 1.2.3 GABAergic system in schizophrenia…………………….….. 17 1.2.4 GABA Receptor……………………………………….......… 18 1.2.5 GABA Transporter……………………………………...…… 20 1.3 GAD……………………………………………………………….... 22 1.3.1 Origin of GAD……………………………………...……….. 22 1.3.2 The GAD65 and GAD67 Genes and Protein Expression….... 22 1.3.3 Regulatory of GAD65 and GAD67…………………………. 23 1.3.4 GAD Expression in Schizophrenia and Related Disorders….. 24 1.3.5 GAD Autoantibody in Stiff-man Syndrome………..……….. 27 1.3.6 GAD Autoantibody in Other Neurological Disorders……..… 30 1.3.7 GAD Autoantibody in Diabetes…………………………...… 32 1.4 ADRA1A…………………………………………………………… 37 1.4.1 Introduction………………………………………………….. 37 1.4.2 ADRA1A Gene Expression and Related Diseases………….. 38 1.4.3 ADRA1A Gene and Metabolic Syndrome in Schizophrenia... 44 1.5 Purpose………………………………………………………...……. 47 第二章 材料與方法…………...……………………………………….......…… 49 2.1 Study population…………………………………………...….....…. 49 2.2 Variables………………………………………………………..…… 49 2.3 Clinical Test………………………………………………….……… 50 2.4 DNA Extraction………………………………………………….….. 51 2.5 dsDNA Quantitation………………………………………………… 52 2.6 Single Nucleotide Polymorphism Seletion……………………….… 52 2.7 Primer design and SNP Detection…………………………..………. 55 2.8 Statistics………………………………………………………..…… 57 2.9 GAD65 Autoantibody Detection……………………………...…….. 58 第三章 結果……………………………………………………....…………….. 59 3.1 GAD65 and GAD67………………………………………………… 59 3.1.1 Haploview Analysis of SNPs in GAD65 Gene……………… 59 3.1.2 Haploview Analysis of SNPs in GAD67 Gene……………… 59 3.1.3 The correlation between the SNPs of GAD and Blood Sugar.. 60 3.1.4 The correlation between the SNPs of GAD and Lipid……..... 62 3.2 ADRA1A…………………………………………………….……… 64 3.2.1 The average of monthly BMI………….…………………….. 64 3.2.2 The correlation between the variables and BMI…………….. 65 3.2.3 Haploview Analysis of SNPs in ADRA1A Gene………….… 66 3.2.4 The correlation between the SNPs of ADRA1A and BMI....... 66 第四章 討論…………………………………………………………………….. 69 4.1 GAD……………………………………………………………..….. 69 4.2 ADRA1A……………………………………………………………. 78 參考文獻………………………………………………………………..………… 84 圖目錄 圖一：以 PicoGreen 定量 dsDNA 的標準曲線………….…………………….. 122 圖二：GenomeLab SNPstream genotyping platform偵測螢光反應後電腦判定結果 ………………………………………………………………………….…. 123 圖三：LD plot in D¢ demonstrating adjacent strength between SNP-pairs at the GAD65 gene……………………………………………………………. 124 圖四：Haplo-blocks, haplotype frequencies between blocks at the GAD65 gene. 125 圖五：LD plot in D¢ demonstrating adjacent strength between SNP-pairs at the GAD67 gene………………………………………………………...….. 126 圖六：Haplo-blocks, haplotype frequencies between blocks at the GAD67 gene. 127 圖七：Significance of GAD65 SNPs in glucose、HbA1c and insulin evaluated by genotype distribution………………………………………………..….. 128 圖八：Significance of GAD67 SNPs in glucose、HbA1c and insulin evaluated by genotype distribution…………………………………………………… 129 圖九：Significance of GAD65 SNPs in cholesterol、triglyceride、HDL and LDL evaluated by genotype distribution…………………………………..… 130 圖十：GAD65 SNPs 與 cholesterol、triglyceride 及 LDL 相關性之比較….. 131 圖十一：GAD65 SNPs 與 cholesterol 及 LDL 相關性之比較…………….. 132 圖十二：Significance of GAD67 SNPs in cholesterol、triglyceride、HDL and LDL evaluated by genotype distribution………………………………..…. 133 圖十三：平均 BMI 及標準差…………………………………...……………. 134 圖十四：LD plot in D¢ demonstrating adjacent strength between SNP-pairs at the ADRA1A gene………………………………………………….…… 135 圖十五：Haplo-blocks, haplotype frequencies between blocks at the ADRA1A gene……….…………………………………………………………... 136 圖十六：Significance of ADRA1A SNPs in BMI evaluated by genotype distribution ………………………………………………………...……………... 137 圖十七：Significance of ADRA1A SNPs in BMI evaluated by allele distribution ……………………………………………………………………….... 138 圖十八：Metabolic highway 理論圖………………………………………….… 139 圖十九：膽固醇及三酸甘油脂之代謝路徑…………………………………….. 140 表目錄 表一：研究個案之基本資料…………………………..………………………… 141 表二：研究個案進行各項臨床檢驗的時間及項目…………………..………… 144 表三：GAD65 基因型分佈與血糖相關檢驗值具有相關性之 SNP 及其統計結果 ………………………………………………………………………….... 145 表四：GAD65 基因型分佈與血脂肪相關檢驗值具有相關性之 SNP 及其統計結 果………………………………………………………………………… 149 表五：GAD67 基因型分佈與血糖及血脂肪相關檢驗值具有相關性之 SNP 及其 統計結果…………………………………………...……………………. 150 表六：ADRA1A 基因型分佈與 BMI 具有相關性之 SNP 及其統計結果.... 151 表七：ADRA1A 對偶基因型分佈與 BMI 具有相關性之 SNP 及其統計結果 ……………………………………………………………...……………. 155 附錄 附錄一：GAD65 SNPs 詳細資訊…………………………………………….… 158 附錄二：GAD67 SNPs 詳細資訊……………………………………..…….….. 160 附錄三：ADRA1A SNPs 詳細資訊…………………………………………….. 162 附錄四：偵測 GAD65 SNPs 之引子及探針…………………………………... 166 附錄五：偵測 GAD67 SNPs 之引子及探針………………………………...… 169 附錄六：偵測 ADRA1A SNPs 之引子及探針……………………………….... 172 附錄七：ADRA1A gene is associated with BMI in chronic schizophrenia patient exposed to antipsychotics……………………………………………... 178 | |
| dc.language.iso | zh-TW | |
| dc.subject | 精神分裂症 | zh_TW |
| dc.subject | 糖尿病 | zh_TW |
| dc.subject | 肥胖 | zh_TW |
| dc.subject | GAD | zh_TW |
| dc.subject | ADRA1A | zh_TW |
| dc.subject | 抗精神病藥物 | zh_TW |
| dc.subject | ADRA1A | en |
| dc.subject | Schizophrenia | en |
| dc.subject | Antipsychotics | en |
| dc.subject | Obesity | en |
| dc.subject | Diabetes | en |
| dc.subject | GAD | en |
| dc.title | 慢性精神分裂症患者肥胖相關臨床表現與候選基因之相關性研究 | zh_TW |
| dc.title | An Association Study of Obesity-related Phenotypes and Candidate Genes in Antipsychotics-treated Chronic Schizophrenia Patients | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 羅爾維,藍祚鴻,郭泰志,邱獻章 | |
| dc.subject.keyword | 精神分裂症,抗精神病藥物,肥胖,糖尿病,GAD,ADRA1A, | zh_TW |
| dc.subject.keyword | Schizophrenia,Antipsychotics,Obesity,Diabetes,GAD,ADRA1A, | en |
| dc.relation.page | 187 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-02-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 病理學研究所 | zh_TW |
| 顯示於系所單位： | 病理學科所 | |
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