研究背景:
雙極症是一種嚴重且失能的精神疾病。以往對於雙極症的病程研究發現，第二型雙極症患者較第一型雙極症患者有較長的發病時期、病程較為慢性、較常發作憂鬱期並常合併極高的自殺風險 (suicide risk)，其自殺嘗試行為(suicide attempt) 的終生盛行率甚至可高達25%至50%，高於單極憂鬱症的所報導的15%，更是一般人口自殺率的15倍之多。臨床上，雙極症的錯誤診斷與不當治療極為常見，有研究指出有接近40%的雙極症病患曾經被誤診為單極憂鬱症。而以往的研究顯示可能需花費平均7.5年的時間才能得到正確診斷與治療，特別是雙極症第二型(bipolar II subtype)的病患。因此如何提高對躁鬱症患者的正確診治率，以減低其自殺風險，已是一個刻不容緩的議題。
過去對於雙極症的病因研究顯示基因扮演一個重要的決定因素。來自於家庭與族譜(family pedigree) ,雙胞胎 (twin study)與領養 (adoption study)的研究指出雙極症是具有高度遺傳性的。血清素系統的異常，已經被證實牽涉到情緒疾患的病理過程。而研究涉入雙極症病理系統與血清素相關的眾多基因中，又以負責產生血清素接受器(serotonin receptor)、血清素轉運子(serotonin transporter)與其代謝酶的基因被認為是主要的候選基因。血清素轉運子在神經組織中的功能是將突觸間隙的血清素運轉回神經元內，藉此調控血清素在突觸間隙的作用時間和強度。而血清素1B 接受器則因突觸間隙間的血清素含量的多寡來調節血清素的釋放，對於血清素在神經組織中的代謝分解則是先經由MAO催化血清素成5-HIAL，再快速的經由乙型乙醛去氫酶(ALDH2)氧化成5-HIAA後釋放至腦脊髓液中。三個重要的基因都參與神經組織中血清素含量的調節。
研究目的:
本研究將雙極症患者詳加區分為第一型雙極症與第二型雙極症，並以分別位於三個基因serotonin transporter (5-HTT) ,5-HTR1B與ALDH2上的三個重要的多型性基因位置(5-HTTLPR, G861C, Glu487Lys)的交互作用來研究三個基因與雙極症的關係。

研究方法:
本研究使用個案對照的研究設計，分別自成大精神科門診及社區收取第一型雙極症102名與第二型雙極症個案160名，社區控制組101名，使用χ2 檢定比較四組在血清素運轉子(5-HTTLPR)基因型頻率、血清素IB接受器(G861C)基因型頻率與乙醛去氫酶2 (Glu487Lys) 基因型頻率的分佈上在雙極症與正常控制組的差異。再以邏輯式回歸分析統計探討此三個基因與雙極症的相關性與其之間的交互作用。
研究結果:
(1). 第一型雙極症與第二型雙極症與正常控制組相比在5-HTT (5-HTTLPR) 、5-HTR1B (G861C)與ALDH2 (Glu487Lys) 基因型頻率分布結果，發現第一型雙極症樣本與正常控制組相比在ALDH2 (Glu487Lys)的1*1基因型有p=0.042的統計顯著值。
(2) 第一型雙極症與第二型雙極症與正常控制組相比在5-HTT (5-HTTLPR)、5-HTR1B (G861C)與ALDH2 (Glu487Lys)的疾病相關性方面，發現第一型雙極症樣本與正常控制組相比在ALDH2 (Glu487Lys) 的1*1基因型有p=0.043的統計顯著值。
(3). 第一型雙極症與第二型雙極症與控制組相比在5-HTT (5-HTTLPR)、5-HTR1B (G861C)與ALDH2 (Glu487Lys) 基因型的交互作用結果，均沒有顯著差異，顯示三個基因在本實驗樣本中並未存在著基因的交互作用影響。
研究討論:
本研究發現，ALDH2 (Glu487Lys)的1*1 基因型在第一型雙極症樣本與正常控制組的基因頻率相比有統計上顯著的不同，表示著ALDH2 (Glu487Lys)的1*1 基因型對第一型雙極症可能存在著影響作用，而在基因與疾病的相關統計中，也同樣存在著顯著的差異，但是此種情況並不存在於第而二型雙極症的樣本中，可能顯示著ALDH2 (Glu487Lys)的1*1 基因型在本研究中的取樣樣本中，可能為第一型雙極症的易感基因。

英文摘要
Background:
Bipolar disorder is a serious and disabling psychiatric disease. Previous studies on course of bipolar disorder showed that patients with bipolar II (BP II) had longer duration of symptomatic period, more rapid-cycling features, more chronic course of illness, more depressive episodes, and high suicide risk, the prevalence rate of suicide attempt in BPII was as high as the range of 25% and 50%, it is more than the depression of 15%, even 15 fold to the community people. In current clinical practice, misdiagnosis and inappropriate treatment of bipolar disorder is very common; previous studies indicated that there are almost 40% of bipolar disorder patients were misdiagnosed with major depression , studies displayed that it took 7.5 years for these patients to receive the correct diagnosis and treatment. Thus in order to lower the suicide risk of BP, how to enhance the correct diagnostic rate of these patients demands immediate attention.
Many studies indicated that genes play an important role in bipolar disorder. Family pedigree, twin studies and adoption studies suggested that bipolar disorder is highly heritable. The dysfunction of serotonergic system has been proved to involve in the progress of pathology of mood disorder. Those of candidate genes of serotonergic system in bipolar disorder suggested that the serotonin receptor, serotonin transporter and enzyme of catabolism play the decisive role. Serotonin transporter transports serotonin from the synaptic cleft back to the neuron to operate the function and intensity in synaptic cleft. Serotonin 1B receptor operated and release serotonin in synaptic cleft. The catabolism of serotonin in neural tissue would catalyze through the MAO to 5-HIAL and rapidly oxidized to 5-HIAA via ALDH, finally release to cerebrospinal fluid (CFS). Those three important gene are all involved in operating the amount of serotonin in neural tissue.
The aim:
We distinguished the bipolar disorder to bipolar I and II, and calculated the interaction via three polymorphism of serotonin transporter, serotonin 1B receptor and ALDH2 gene to explore the association of this three genes with bipolar disorder.
Methods:
Case-control study would be used , 102 of bipolar I patients and 160 of bipolar II patients was recruited from the clinic and 101 volunteers from the community to serve as the control group. Genotype distribution of the three polymorphisms in the serotonin transporter, serotonin 1B receptor and ALDH2 gene were compared between groups and control using Pearson χ² analysis. The interaction of three genes and the association of gene and disease were analytic with logistic regression.
Results:
A significant difference was found between the *1*1 genotype of ALDH2 gene and bipolar I with p=0.042 and the same situation is also existed in the association data with disease. However, there were no significant gene interaction among three groups.
Conclusions:
The *1*1 genotype of ALDH2 gene may a risk factor for bipolar I disorder.

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