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研究生:黃長治
研究生(外文):HUANG, CHANG-CHIH
論文名稱:探討基因多形性、環境壓力及臨床特徵對物質使用疾患之影響
論文名稱(外文):Exploring the impact of genetic polymorphisms, environmental stress, and clinical characteristics in substance use disorders
指導教授:黃三原黃三原引用關係
指導教授(外文):HUANG, SAN-YUAN
口試委員:萬芳榮蔡尚穎顏正芳蔡世仁黃三原
口試委員(外文):WAN, FANG-JUNGTSAI, SHANG-YINGYEN, CHENG-FANGTSAI, SHIH-JENHUANG, SAN-YUAN
口試日期:2018-12-21
學位類別:博士
校院名稱:國防醫學院
系所名稱:醫學科學研究所
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:2019
畢業學年度:107
語文別:英文
論文頁數:111
中文關鍵詞:酒精依賴海洛因依賴多巴胺轉運體基因類鴉片相關基因人格特質環境壓力晚發型
外文關鍵詞:Alcohol dependenceHeroin dependenceDAT1 geneopioid related genespersonality traitslife stresslate onset
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背景: 物質使用疾患的成因是多元的且與基因和環境因素有關。腦內多巴胺及類鴉片系統失調分別被認為在酒精依賴及海洛因依賴的病因中扮演重要的角色。本研究的目的是:一、探討多巴胺轉運體基因是否會影響酒精依賴及其次族群(早發型或晚發型)的易感受性以及基因型變異是否會影響酒精依賴病人的人格特質;二、探討類鴉片相關基因(OPRM1、OPRD1、OPRK1及POMC)之基因型變異是否會影響海洛因依賴的易感受性以及影響海洛因依賴病人對環境壓力的感受及反應。
方法:本研究使用對偶基因頻率分析、基因型分佈分析、邏輯回歸分析及單套體基因型分析來評估基因型變異與疾病易感受性的相關聯性。我們分別在637名酒精依賴病人及523名健康受試者使用了16個單核苷酸多型性以及801名海洛因依賴病人及530名健康受試者使用了10個單核苷酸多型性來進行分析。並使用三向度人格量表來評估酒精依賴病人的人格特質(追求新奇和逃避傷害)、生活壓力量表來評估海洛因依賴病人對近一年環境壓力的感受及反應。
結果:我們發現多巴胺轉運體基因型rs6350與酒精依賴相關(P < 0.05)。進一步的次族群分析發現確認此關聯只有與晚發型酒精依賴有關(P = 0.003),而跟早發型酒精依賴無關。邏輯回歸分析顯示rs6350 的A異型受試者比沒有A對偶其因的受試者有高出近3倍的危險發生晚發型酒精依賴。雖然我們發現酒精依賴病人跟健康受試者比有較高的追求新奇和逃避傷害人格特質分數(P < 0.001),但是我們使用線性回歸分析並沒有發現DAT1基因多型性會影響酒精依賴病人的追求新奇和逃避傷害人格特質。我們也在對偶基因頻率分析及基因型分佈分析發現OPRD1 rs2234918的C對偶基因在海洛因病人組有過度表現的情形(P = 0.006及P = 0.002)。此發現被後續的邏輯回歸分析所確認,顯示帶有C對偶基因的受試者比T/T基因型的受試者有高出1.42倍的危險發生海洛因依賴。此外,海洛因病人比健康受試者有更高的負向事件發生數(No)、負向事件壓力嚴重度(Ns)、單一負向事件壓力嚴重度(Na)(所有P < 0.001),但是在正向事件兩組則沒有差異。在海洛因組基因壓力評估顯示OPRD1 rs2236857的T/T基因型受試者比C對偶基因受試者有更高的環境壓力(Ns, P = 0.004和Na, P = 0.047)。
結論:本研究結果顯示在台灣漢民族DAT1基因多型性可能會影響晚發性酒精依賴的易感受性;而OPRD1基因多型性可能不只在海洛因依賴成因扮演重要的角色,並且會影響海洛因依賴病人對環境壓力的反應。

Background: The etiology of substance use disorders is multifactorial and associated with different environmental and genetic factors. Dopaminergic and opioid system dysfunctions have been considered important roles in the pathogenesis of alcohol dependence (AD) and heroin dependence (HD), respectively. The purposes of the present study were to determine whether the dopamine transporter (DAT1) gene was associated with AD or its subgroups, namely early-onset AD (EOAD) and late-onset AD (LOAD), and its variants were associated with specific personality traits in patients with AD; and whether variants of the opioid related genes (OPRM1, OPRD1, OPRK1, and POMC) could affect vulnerability to HD and response to life stress in patients with HD.
Methods: Allele frequency, genotype distribution, logistic regression, and haplotype analyses were used to determine the association of gene variants and disease vulnerability. We used sixteen polymorphisms in DAT1 gene in 637 patients with AD and 523 healthy controls, and ten polymorphisms of the opioid related genes in 801 patients and 530 controls, respectively. The Tridimensional Personality Questionnaire (TPQ) was used to assess the personality traits novelty seeking (NS) and harm avoidance (HA) in the patients with AD. The Life Event Questionnaire (LEQ) was used to assess the perspective and response to life stress in the past year.
Results: We found evidence of association between DAT1 rs6350 and AD (P < 0.05). Following subgroup analysis, we confirmed evidence of an association in patients with LOAD (P = 0.003), but not in patients with EOAD. Heterozygous carriers of the A allele have a nearly 3 times greater risk to develop LOAD compared to individuals who do not have an A allele. Although we found that patients with AD had higher NS and HA scores compared to controls (P < 0.001), we did not find evidence of association between DAT1 polymorphisms and either NS or HA in patients with AD using linear regression analysis. We also found that the minor C allele of rs2234918 in OPRD1 is over-represented in the HD group by genotype distribution and allelic frequency analyses (P = 0.006 and P = 0.002, respectively). This finding was further confirmed by logistic regression analysis, showing that C allele carriers have a 1.42 times greater risk for HD compared to T/T homozygotes. Patients with HD have a higher occurrence of negative events (No), negative events score (Ns), and average negative event score (Na) than those of controls (all P <0.001), but there was no difference regarding positive recent events between the two groups. Gene-stress assessment in the HD group showed that T/T homozygotes of OPRD1 rs2236857 have more severe stress than C allele carriers (Ns, P = 0.004 and Na, P = 0.047).
Conclusions: Our results indicate that the DAT1 gene may have a role in susceptibility to late-onset AD, and that the OPRD1 gene may not only play a role in the pathogenesis of HD but also affect the response to life stress among patients with HD in our Han Chinese population.

Index of Contents
Index of Contents I
List of Tables III
List of Figures V
Chinese Abstract VI
English Abstract VIII
List of abbreviations XI
1. Introduction 1
1.1. Background 1
1.2. Association among Genetic Variants of DAT1 gene, personality Traits, and age of onset in patients with AD 4
1.2.1. Dopamine system and AD 4
1.2.2. The role of DAT1 gene and AD 5
1.2.3. Clinical characteristics: age of onset in patients with AD 6
1.2.4. Clinical characteristics: personality traits in patients with AD 7
1.3. Association between Genetic Variants of opioid related genes and environmental stress in patients with HD 8
1.3.1. Opioid system and HD 8
1.3.2. The role of opioid related genes and HD 9
1.3.3. Environmental stress in patients with HD 11
1.4. Study aims 12
2. Materials and Methods 13
2.1. Participants 13
2.1.1. Patients with substance use disorders 13
2.1.2. Healthy controls 13
2.2. Interview Screening Tool 14
2.3. The Psychometric Assessment 14
2.3.1. TPQ 14
2.3.2. LEQ 17
2.4. Blood sampling for genotyping 18
2.4.1. SNPs selection for DAT1 gene 20
2.4.2. SNPs selection for opioid related genes 21
2.4.3. SNPs genotyping with PCR 21
2.5. Statistical Analyses 23
2.5.1. Statistical Analyses for Investigating the Association between genetic Variants and Substance use disorders 23
2.5.2. Statistical Analyses for gene-personality and gene-stress assessments 24
3. Results 25
3.1. Association among Genetic Variants of DAT1 gene, personality Traits, and age of onset in patients with AD 25
3.1.1. Demographic data 25
3.1.2. Single marker analysis for DAT1 variants and AD 25
3.1.3. Single marker analysis for DAT1 variants and subgroups of AD 26
3.1.4. Haplotype analysis for DAT1 variants and AD 27
3.1.5. Comparison of personality scores between patients with AD and controls 27
3.1.6. Relationship between DAT1 variants and personality scores 28
3.2. Association between Genetic Variants of opioid related genes and environmental stress in patients with HD 29
3.2.1. Demographic data 29
3.2.2. Single marker analysis for variants of opioid related genes and HD 29
3.2.3. Haplotype analysis for variants of opioid related genes and HD 30
3.2.4. Environmental stress assessment between the HD and control groups 31
3.2.5. Relationship between variants of opioid related genes and environmental stress in patients with HD 31
4. Discussion 32
4.1. The DAT1 gene possibly affects vulnerablity to LOAD but not specific personality traits in our Han Chinese Population 32
4.1.1 Variants of DAT1 gene and AD vulnerability 32
4.1.2 The role of DAT1 variants to affect age of onset in patients with AD 36
4.1.3 Variants of DAT1 gene and specific personality traits in patients with AD 39
4.2. OPRD1 gene affects disease vulnerability and environmental stress in patients with HD 41
4.2.1 Variants of opioid related genes and HD vulnerability 41
4.2.2 Environmental stress between patients and controls 45
4.2.3 Opioid related genes and life stress in patients with HD 46
4.3. Limitations 49
5. Conclusion 52
References 53
Tables 72
Figures 83
Appendix 87


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