白血球粒線體去氧核醣核酸拷貝數、多形性，氧化傷害與情感性疾患的關聯性探討

The Association of Leukocyte Mitochondrial DNA Copy Number, Polymorphisms, and Oxidative Damage in Affective Disorders

張正辰

粒線體 ； 氧化傷害 ； 雙極性疾患 ； 重鬱症 ； mitochondria ； oxidative damage ； bipolar disorder ； major depressive disorder

中山醫學大學醫學研究所學位論文

2016年

博士

賴德仁

英文

研究目的： 本研究分成兩部分，第一部份比較第一型雙極性疾病患者與正常對照組的白血球粒線體DNA的拷貝數，單核苷酸多型性和氧化傷害的變化。第二部分則比較重鬱症病患與正常對照組的不同。 研究方法及資料：研究方法為個案對照研究，個案組來自中部某醫學中心精神科門診病患，符合DSM-IV精神科診斷手冊第一型雙極性疾患和重鬱症的診斷。納入條件為病情穩定而且在過去兩個月皆未改變精神科用藥。排除條件為藥物導致的精神病，飲食疾患，焦慮症或非法藥物濫用者。個案組與對照組皆無慢性身體疾病，無急性感染，且無懷孕。對照組來自身體健康的體檢個案，過去未有重大精神疾患，並且無抽菸。藉著周邊白血球分析，比較個案組與對照組的粒線體DNA的拷貝數，單核苷酸多型性和氧化傷害的變化。 研究結果： 本研究共招募四十名雙極性疾病患者，四十名重鬱症病患和七十名健康對照組患者。他們的年齡中位數分別是41.5, 42 and 38 歲。雙極性疾患和重鬱症患者的白血球粒線體DNA的拷貝數明顯比對照組患者要低 (p<0.001 and p=0.037)。 雙極性疾患和重鬱症患者都比對照組患者有較高的氧化傷害 (p<0.001)。病人組和健康對照組的C5178A和A10398G粒線體單核苷酸多型性比較並無差異。經廣義線性模型控制相關變項後，雙極性疾患和重鬱症患者的白血球粒線體DNA的拷貝數仍比對照組患者明顯降低。另外，粒線體DNA的氧化傷害與年齡成正相關。重鬱症患者的粒線體DNA的拷貝數與抗精病藥物使用呈負相關(p=0.036)。 結論與建議： 氧化傷害和粒線體功能異常可能與雙極性疾病，重鬱症的病理生理學有關連，這需要更大規模的研究證實。未來研究情感性疾患的粒線體功能異常也許可發展為生物指標。本研究之限制為橫斷面研究，僅為相關性探討，缺乏縱貫面追蹤，無法作為因果歸因；另外本研究病患病況穩定，所以本研究結果運用到其他族群需要留意。

Aims: This dissertation consists of two parts: (1) To compare alterations of mitochondria DNA (mtDNA) copy number, single nucleotide polymorphisms (SNPs), and oxidative damage of mtDNA in clinically stable patients with bipolar I disorder (BD) and normal controls. (2) The same research topics were investigated between patients of major depressive disorder (MDD) and normal controls. Methods: Patients met DSM-IV diagnostic criteria for BD and MDD were recruited from the psychiatric outpatient clinic at a medical center in Central Taiwan. They were clinically stable and their medications had not changed for at least the preceding two months. Exclusion criteria were substance-induced psychotic disorder, eating disorder, anxiety disorder or illicit substance abuse. All participants had no history of chronic medical illness, no indication of acute infection and were not pregnant. Comparison subjects did not have any history of major psychiatric disorders and they were non-smokers. By analyzing peripheral blood leukocytes, copy number, SNPs and oxidative damage of mtDNA were compared between patients and controls. Results: Forty BD patients, 40 MDD patients and 70 comparison subjects were included in this study. The median age of the subjects was 42, 41.5 and 38 years in MDD, BD and comparison groups, respectively. Leukocyte mtDNA copy number was significantly lower in BD and MDD patients than that of the comparison group (p<0.001 and p=0.037). All patients had significantly higher mitochondrial oxidative damage than the comparison group. The SNP of mtDNA C5178A and A10398G were similar in patients and control groups. After generalized linear model adjusting with related variables, mtDNA copy number was still significantly lower both in BD (p<0.001) and MDD group (p<0.001). MtDNA oxidative damage was positively correlated with age. Antipsychotic use was negatively associated with mtDNA copy number (p=0.036) in MDD group. Conclusions and Suggestions: Possible involvement of oxidative damage and mitochondria in the pathophysiology of BD and MDD needs more large-scale studies. Future study of mitochondrial dysfunction in affective disorders may bring some light in the development of disease biomarker. The study is cross-sectional with no longitudinal follow up. This relationship between mitochondrial dysfunction and affective disorders was correlational instead of causal. The study cohort is clinically stable and generalizability of our result to other cohort should be cautiously considered.

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