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系統識別號 U0026-0812200914285127
論文名稱(中文) 瘦素受體基因多型性與躁鬱症患者服用情緒穩定劑引起代謝異常之關聯性研究
論文名稱(英文) The Association Between Leptin Receptor Gene Polymorphisms and Mood Stabilizers Induced Metabolism Abnormalities in Patients with Bipolar Disorder
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 96
學期 2
出版年 97
研究生(中文) 張琦偉
研究生(英文) Chi-wei Chang
學號 s2695112
學位類別 碩士
語文別 中文
論文頁數 91頁
口試委員 口試委員-周辰熹
口試委員-陳柏熹
指導教授-簡伯武
中文關鍵字 瘦素受體  基因多型性  躁鬱症患者 
英文關鍵字 Bipolar Disorder  Gene Polymorphisms  Leptin Receptor 
學科別分類
中文摘要 丙戊酸和鋰鹽屬於情緒穩定劑,常用於躁鬱症的治療。丙戊酸和鋰鹽主要的副作用是引發病人代謝異常,但代謝異常發生與否常因人而異。本篇研究想探討和攝食行為及能量代謝有關的瘦素受體基因之單一位點核苷酸變異,是否與服用情緒穩定劑所引起的代謝異常有關。
由國立成功大學附設醫院招募117位符合DSM-IV診斷標準的躁鬱症病人,測量病人的代謝指標及定序由Hapmap project 網站上挑選之瘦素受體基因單一位點核苷酸變異。挑選之瘦素受體基因單一位點核苷酸變異之連結性不平衡和haplotypes則由Haploview程式分析。接著本研究利用SPSS軟體分析各代謝指標和瘦素受體基因單一位點核苷酸變異之基因型是否有關;最後則利用SPSS軟體分析代謝指標和血中藥物濃度之關聯性在特定瘦素受體單一位點核苷酸變異的三個基因型之間是否有顯著差異。
結果發現瘦素受體單一位點核苷酸變異 rs1327121、rs8179183及rs4655555各基因型之比例在病人與健康受試者間有顯著差異。而這三個位點所構成的haplotype AGT在健康受試者所占的比例顯著高於躁鬱症病人,表示相較於其它haplotype,AGT可能是和躁鬱症關聯性較小的基因標誌。接著發現瘦素受體單一位點核苷酸變異rs12145690、rs9436747和rs8179183之各基因型比例與特定代謝指標間有顯著的關聯性。這個結果暗示瘦素受體基因上的單一位點核苷酸變異和服用情緒穩定劑後之躁鬱症病患的代謝異常有關。最後則是發現代謝指標和血中丙戊酸濃度之關聯性在rs1327122及rs9436747的三個基因型之間有顯著差異。此結果暗示服用丙戊酸可能在不同瘦素受體基因型的病人中引起不同的代謝改變。
本篇研究的結果顯示瘦素受體基因之單一位點核苷酸變異與躁鬱症及服用情緒穩定劑所引起的代謝改變有關。
英文摘要 Valproic acid and lithium are mood stabilizers that were used for bipolar patients. The major side effect of valprioc acid and lithium is medication induced metabolic abnormalities. However, the effect is variable between individuals. In our study, we try to test whether single nucleotide polymorphisms (SNPs) of the leptin receptor (LEPR) gene that corresponding to feeding behavior and energy expenditure are associated with the metabolic abnormalities caused by mood stabilizers.
Subjects (n=117) meet the DSM-IV criteria for bipolar disorder were recruited from the National Cheng Kung University Hospital. Metabolic indexes were measured. Specific SNPs of the LEPR chosen from Hapmap project were genotyped. The linkage disequilibrium and haplotypes of the SNPs were first estimated by the Haploview program. Then we tested the possible associations between genetic variances and metabolic indexes analyzed by SPSS program.
Results showed the genotype frequencies of the rs1327121, rs8179183 and rs4655555 variances were significantly different between patients and control. Besides, the frequency of haplotype AGT composed of rs1327121, rs8179183 and rs4655555 were significantly higher in control than in the patient group. It suggested that people who own haplotype AGT might be protected from bipolar disorder.
Variances of the rs12145690, rs9436747 and rs8179183 were associated with metabolic indexes in patients, these variances might relate to the metabolic changes of bipolar patients taking mood stabilizers. The correlation between metabolic indexes and plasma valproate levels were significantly different among different rs1327121 and rs9436747 genotypes. These results indicated that valproate might induce different metabolic responses in different LEPR genotypes.
Our study indicated SNPs of LEPR gene were associated with bipolar disorder and metabolic changes induced by mood stabilizers.
論文目次 中文摘要.................................................I
英文摘要................................................II
目錄...................................................III
第一章 序論.............................................1
第一節 躁鬱症的症狀及藥物治療............................2
第二節 瘦素及瘦素受體....................................4
第三節 藥物基因體學......................................4
第四節 研究目的..........................................6
第二章 研究材料及方法 ..................................7
第一節 病患及健康受試者之招募及檢測.....................8
第二節 單一位點核苷酸變異檢測..........................11
第三節 統計分析........................................17
第三章 結果............................................19
第一節 躁鬱症病人及健康受試者之資料統計................20
第二節 瘦素受體基因單一位點核苷酸變異之基因型頻率......20
第三節 瘦素受體基因單一位點核苷酸變異位點間的連結性....21
第四節 瘦素受體基因單一位點核苷酸變異所組成之haplotype
分析............................................22
第五節 瘦素受體基因單一位點核苷酸變異和代謝指標間的關
係..............................................23
第六節 瘦素受體基因單一位點核苷酸變異對藥物血中濃度與代
謝指標高低間關聯的影響..........................25
第四章 結論.............................................27
第五章 討論.............................................30
參考文獻.................................................42
圖索引...................................................48
表索引.................................................. 64
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