本文選題：馬查多-約瑟夫�。∕JD） + APOE基因多態(tài)性��； 參考：《福建醫(yī)科大學》2014年碩士論文

【摘要】：目的: 研究載脂蛋白E基因多態(tài)性與中國漢族人群馬查多-約瑟夫�。∕JD）患者發(fā)病年齡的關系及報道并分析一例純合的馬查多-約瑟夫病患者的臨床特點。 方法： 收集來自2005-2013年復旦大學附屬華山醫(yī)院和福建醫(yī)科大學附屬第一醫(yī)院門診及住院部經(jīng)基因檢測確診的362個家系的403例MJD患者。采用聚合酶鏈反應（PCR）擴增ATXN3基因10號外顯子部分序列，，對擴增后產(chǎn)物進行直接測序或割膠回收后測序來確定CAG重復數(shù)。應用多重熒光PCR限制性片段長度多態(tài)性分析的技術進行APOE基因分型。利用相關統(tǒng)計手段探討與MJD發(fā)病年齡變異性相關的因素及報道并分析一例純合的MJD患者的臨床特點。 結果： 1.所有403例MJD患者的平均發(fā)病年齡為36.28±0.56（10-72）歲。異常擴增的ATXN3等位基因的平均CAG重復數(shù)是75.90±0.186（53-87）。 2.異常擴增的ATXN3等位基因的CAG重復數(shù)與MJD患者發(fā)病年齡呈負相關（R2=0.659, p=0.000），能解釋65.9%的發(fā)病年齡變異性。 3.在調(diào)整ATXN3基因異常擴增的CAG重復數(shù)后，攜帶不同APOE基因型的MJD患者的發(fā)病年齡沒有統(tǒng)計學差異(ANCOVA, F=0.18, p=0.9474)。 4.應用多元線性回歸模型發(fā)現(xiàn)MJD患者的APOE基因型和性別對發(fā)病年齡沒有影響(APOE基因型：p=0.892；性別：p=0.512,)，而異常ATXN3等位基因的CAG重復數(shù)、正常ATXN3等位基因的CAG重復數(shù)及兩者的相互作用對患者的發(fā)病年齡有顯著影響（異常等位基因的CAG重復數(shù)：p=0.000；正常等位基因的CAG重復數(shù)：p=0.043；兩者的相互作用：p=0.035）。相較只含異常等位基因的CAG重復數(shù)的線性回歸模型，能增加MJD患者發(fā)病年齡變異性額外0.7％的解釋作用。 5.262例已知遺傳方式的MJD患者中，父系遺傳患者與母系遺傳患者的發(fā)病年齡存在顯著性的統(tǒng)計學差異(33.5±0.833vs36.6±1.022,p=0.021)，但在調(diào)整異常擴增的CAG重復數(shù)之后，這種顯著性統(tǒng)計學差異消失（(ANCOVA, F=0.043, p=0.835)。 6.純合MJD患者的ATXN3基因的CAG重復次數(shù)為60/60,較具有相同CAG重復數(shù)的雜合MJD患者的發(fā)病年齡明顯提前,且病情進展更快。 結論： 1.異常ATXN3等位基因的CAG重復數(shù)與MJD患者發(fā)病年齡呈負相關，能解釋65.9%的發(fā)病年齡變異性。因此不能作為MJD患者發(fā)病年齡的獨立預測因子 2. APOE基因多態(tài)性與MJD患者發(fā)病年齡不相關，且性別不影響MJD患者的發(fā)病年齡。 3.正常ATXN3等位基因的CAG重復數(shù)、異常ATXN3等位基因的CAG重復數(shù)及兩者的相互作用會影響MJD患者的發(fā)病年齡。 4.遺傳方式會影響患者異常ATXN3的CAG重復數(shù)，父系遺傳患者的異常CAG重復數(shù)大于母系遺傳患者的CAG重復數(shù)。 5.遺傳方式與MJD患者發(fā)病年齡變異性相關。 6.純合的MJD患者中相較于雜合患者，其發(fā)病年齡顯著性提早且病程進展更為迅速。
[Abstract]:Objective: To study the relationship between apolipoprotein E gene polymorphism and the age of onset of Machado Joseph disease (MJDD) in Chinese Han population and to report and analyze the clinical characteristics of a homozygous Machado Joseph disease patient. Methods: A total of 403 MJD patients from the outpatient and inpatient departments of Huashan Hospital affiliated to Fudan University and the first affiliated Hospital of Fujian Medical University from 2005 to 2013 were collected. Exon 10 of ATXN3 gene was amplified by polymerase chain reaction (PCR). The CAG repeats were determined by direct sequencing or gel recovery sequencing. Multiplex fluorescent PCR restriction fragment length polymorphism analysis was used for APOE genotyping. To investigate the factors associated with age variability of MJD and to report and analyze the clinical features of a homozygous patient with MJD. Results: 1. The mean age of onset of all 403 patients with MJD was 36.28 鹵0.56 10-72 years old. The average CAG repeats of the ATXN3 alleles were 75.90 鹵0.186 ~ 53-87. 2. The number of CAG repeats of the abnormal amplified ATXN3 alleles was negatively correlated with the onset age of MJD patients, and could explain 65.9% of the age variability of MJD. 3. After adjusting the number of CAG repeats in abnormal amplification of ATXN3 gene, there was no significant difference in the onset age of MJD patients with different APOE genotypes. 4. The multivariate linear regression model was used to find that the APOE genotype and sex of MJD patients had no effect on the age of onset of the disease. The apo genotype: p0. 892; gender: p0. 512; and the CAG repeats of abnormal ATXN3 alleles. The CAG repeats of normal ATXN3 alleles and their interactions have significant effects on the onset age of the patients (CAG repeats of abnormal alleles: p0. 000; CAG repeats of normal alleles: p0. 043; interaction of the two alleles: p0. 035). Compared with the linear regression model of CAG repeats with only abnormal alleles, it could increase the incidence age variability of MJD patients by an additional 0.7%. In 5.262 MJD patients with known genetic patterns, there was a significant difference in age of onset between patrilineal and matrilineal genetic patients (33.5 鹵0.833vs36.6 鹵1.022) p0. 021, but after adjusting for abnormal amplified CAG repeats, the significant statistical difference disappeared with ANCOVA, FU 0.043, p0.83535. 6. The number of CAG repeats of ATXN3 gene in homozygous MJD patients was 60 / 60, which was significantly earlier than that in heterozygous MJD patients with the same CAG repeats, and the disease progression was faster than that of heterozygous MJD patients with the same CAG repeats. Conclusion: 1. The CAG repeats of abnormal ATXN3 alleles were negatively correlated with the onset age of MJD patients, which could explain 65.9% of the age variability. Therefore, it cannot be used as an independent predictor of onset age in MJD patients. 2. APOE gene polymorphism was not associated with the age of onset of MJD, and gender did not affect the age of onset of MJD. 3. The number of CAG repeats in normal ATXN3 alleles, CAG repeats in abnormal ATXN3 alleles and their interactions may affect the onset age of MJD patients. 4. The number of CAG repeats in patients with abnormal ATXN3 was influenced by genetic pattern, and the number of abnormal CAG repeats in patrilineal patients was greater than that in patients with matrilineal heredity. 5. Genetic patterns were associated with age variability in patients with MJD. 6. In homozygous MJD patients, the onset age was significantly earlier and the course of disease was more rapid than that in heterozygous patients.
【學位授予單位】：福建醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R744.7

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