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研究生:王惠君
研究生(外文):Hui-Chun Wang
論文名稱:台灣地區躁鬱症與血清素轉運蛋白之單核酸多型性分析
論文名稱(外文):Association analysis of single-nucleotide polymorphisms around serotonin transporter gene and bipolar affective disorder in Taiwan.
指導教授:孫孝芳孫孝芳引用關係
指導教授(外文):H. Sunny Sun
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:英文
論文頁數:55
中文關鍵詞:單型分析躁鬱症單核酸多型性血清素轉運蛋白
外文關鍵詞:serotonin transportersingle-nucleotide polymorphismhaplotype analysisbipolar affective disorder
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躁鬱症顧名思義是一種嚴重的情緒障礙,它最明顯的特徵是病患呈現週期性躁期與鬱期交替出現,使其情緒會有兩種極端的變化與擺動。在不同的族群中,躁鬱症的終生發生率約為0.5% ~ 1%;若不加以治療,約有20%之病患會因自殺而死亡,因此也使得躁鬱症成為主要的公共衛生問題之一。先前在雙胞胎、家族史和領養的研究顯示這種疾病具有強烈的遺傳性,但對於此病的致病基因及其在病源學上的影響仍所知有限。有鑑於躁鬱症為情感性疾病,因此神經系統中與調控情緒反應相關的神經傳導物質即為研究病理成因的主要目標。神經傳導物質血清素,因其調控許多生理功能,例如:活動力、飲食、睡眠、生殖能力與情緒反應,使得所有與血清素生成代謝相關的基因,都可用來研究其與情感性疾病的相關性。血清素轉運蛋白在其中扮演舉足輕重的角色,其可將突觸間隙的血清素轉運回神經元內,藉此調控血清素在突觸間隙的作用時間與強度。血清素轉運蛋白之基因位於第十一號染色體長臂11.1-11.2,包含十四個表現序列,總長約有三千一百個鹼基對。血清素轉運蛋白已是發展治療精神疾病藥物的主要標的,諸如憂鬱症、恐慌症以及其他精神疾病均可得到明顯的療效。關於此基因與躁鬱症之間的關係,先前即有科學家證明了5HTTLPR(位於此基因啟動子區域中的一種四十四鹼基對插入或缺失的基因多型性)可調控基因的表現,並且推測其可能是躁鬱症的感受性因子。此外,在我們實驗室小規模的初步研究亦發現5HTTVNTR(位於此基因第二個非表現序列上的隨機重複序列)與台灣地區的躁鬱症有相關性。為了想更深入瞭解血清素轉運蛋白在台灣地區躁鬱症所扮演的角色,我們在此基因周圍共約六萬個鹼基對的區域中挑選了十個標竿,其中包括5HTTLPR,5HTTVNTR和八個單核酸多型性來進行分析。針對單核酸多型性我們使用了三種螢光分析方法來鑑別每一個體之基因型,結果發現有兩個單核酸多型性並不存在於台灣族群中,其餘八個標竿則利用傳統卡方檢定及單型分析來測量其與躁鬱症之相關性。分析結果指出所有在血清素轉運蛋白基因中的標竿與疾病沒有明顯相關性。此外,利用單型評估軟體計算,不論在實驗組或對照組這八個標竿彼此之間存有連鎖不平衡現象。總而言之,本研究結果推測血清素轉運蛋白基因在台灣地區躁鬱症的病源學上並不扮演決定性角色,儘管如此,我們仍不能排除是否有其他的因素影響血清素轉運蛋白基因之表現進而促使躁鬱症的發生,這些問題還有待更多的研究才能夠釐清。
Bipolar affective disorder (BPD), also known as manic-depressive psychosis is the major mental illness after major depression. Little is known about the underlying causes of BPD, the lifetime prevalence has estimated about 0.5% to 1% in various populations. Twin, family pedigree and adoption studies all suggested a strong genetic component for BPD. Serotonin (also known as 5-hydroxytryptamine, 5-HT) is a key neurotransmitter in the central and peripheral nervous system and contributes to various physiological functions such as motor activity, food intake, sleep, reproductive activity and emotion. Genes involved in serotonin transmission and metabolic pathways thus are good candidates for studying their involvement in BPD pathogenesis. Serotonin transporter gene (SLC6A4, a member of solute carrier family) consists of 14 exons spanning about 31 kb on chromosome 11q11.1-11.2 and responds for re-uptaking serotonin into presynaptic terminal thus fine-tuning of brain serotonergic neurotransmission. Serotonin transporter has been the primary target for developing therapeutic medicine for the treatment of depression, panic disorder and other psychiatric disorder. Previous studies have indicated that the 5HTTLPR (a 44 bp insertion/deletion polymorphism in the promoter region of the SLC6A4 gene) alters the gene expression thus suggesting a genetic susceptibility factor for BPD. In addition, our preliminary study also demonstrated that 5HTTVNTR (a variable number of tandem repeat in intron 2 region of the SLC6A4 gene) has associated with BPD in Taiwan. To further analyze the role of gene in the etiology of BPD, 10 markers including 5HTTLPR, 5HTTVNTR and 8 single nucleotide polymorphisms (SNPs) within 60 kb interval surrounding the SLC6A4 gene were selected to study the association with BPD in Taiwan. Three fluorescent-based approaches for SNP genotyping have been used in this study. Among these markers, two SNPs were found not informative in Taiwanese population and eight polymorphic markers have been analyzed by classical chi-square test as well as haplotype analysis. No association can be obtained between all SLC6A4 markers and BPD. In addition, significant linkage disequilibrium (LD) was obtained among 8 markers but not between markers and putative disease loci by using the EH program. This study demonstrates that the SLC6A4 gene may not play an important role in BPD etiology and suggest the other candidate genes different from Caucasian may be involved. Besides, the epistatic interaction effect of SLC6A4 with others factors still cannot be excluded and more analysis will be necessary to formulate the serotonin transporter in BPD pathogenesis.
ABSTRACT IN CHINESEⅠ
ABSTRACT IN ENGILISHⅢ
ACKNOWLEDGEMENTS Ⅴ
LIST OF TABLES Ⅸ
LIST OF FIGURESⅩ
CHAPTER 1 INTRODUCTION 1
1.1 Bipolar affective disorder (BPD) 1
1.2 Epidemiological studies of BPD2
1.3 Molecular genetic studies of BPD ...2
1.3.1 Linkage analysis ...3
1.3.2 Association analysis...4
1.4 Serotonergic neurotransmitter system...4
1.5 Serotonin transporter ...7
1.5.1 Chromosomal location, gene structure and function ...7
1.5.2 Association of serotonin transporter with various diseases ...10
1.5.3 Association study of serotonin transporter with BPD in Taiwan ...11
1.6 Single-nucleotide polymorphisms (SNPs) ...12
1.7 SNP genotyping technologies ...13
1.8 Haplotype analysis ...15
1.9 Specific aims of this study...16
CHAPTER 2 MATERIALS AND METHODS...17
2.1 Sample collection...17
2.2 DNA extraction...17
2.3 Marker selection ..19
2.4 Primer design...19
2.5 PCR amplification...20
2.6 Genotyping ...20
2.6.1 VNTR genotyping...20
2.6.2 DNA sequencing ...22
2.6.3 Multiple single base extension (MSBE)...22
2.6.3.1 Principle ...22
2.6.3.2 Procedure...23
2.6.4 Melting curve analysis ...25
2.6.4.1 Principle ...25
2.6.4.2 Procedure...25
2.7 Statistical analysis..27
CHAPTER 3 RESULTS...28
3.1 Marker selection and primer design..28
3.2 Population-based association analysis .28
3.3 Haplotype analysis .32
CHAPTER 4 DISCUSSION .39
4.1 Comparison of fluorescence-based SNP genotyping methods.39
4.2 Different marker patterns in different populations 40
4.3 Haplotype tag markers around SLC6A4 42
4.4 Pharmacological therapies and BPD42
4.5 SLC6A4 gene effect in the etiology of BPD44
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