载脂蛋白E基因多态性与中国汉族人群马查多—约瑟夫病临床表型关系的研究

发布时间：2018-05-22 12:40

本文选题：马查多-约瑟夫病（MJD） + APOE基因多态性　；参考：《福建医科大学》2014年硕士论文

【摘要】：目的: 研究载脂蛋白E基因多态性与中国汉族人群马查多-约瑟夫病（MJD）患者发病年龄的关系及报道并分析一例纯合的马查多-约瑟夫病患者的临床特点。方法：收集来自2005-2013年复旦大学附属华山医院和福建医科大学附属第一医院门诊及住院部经基因检测确诊的362个家系的403例MJD患者。采用聚合酶链反应（PCR）扩增ATXN3基因10号外显子部分序列，，对扩增后产物进行直接测序或割胶回收后测序来确定CAG重复数。应用多重荧光PCR限制性片段长度多态性分析的技术进行APOE基因分型。利用相关统计手段探讨与MJD发病年龄变异性相关的因素及报道并分析一例纯合的MJD患者的临床特点。结果： 1.所有403例MJD患者的平均发病年龄为36.28±0.56（10-72）岁。异常扩增的ATXN3等位基因的平均CAG重复数是75.90±0.186（53-87）。 2.异常扩增的ATXN3等位基因的CAG重复数与MJD患者发病年龄呈负相关（R2=0.659, p=0.000），能解释65.9%的发病年龄变异性。 3.在调整ATXN3基因异常扩增的CAG重复数后，携带不同APOE基因型的MJD患者的发病年龄没有统计学差异(ANCOVA, F=0.18, p=0.9474)。 4.应用多元线性回归模型发现MJD患者的APOE基因型和性别对发病年龄没有影响(APOE基因型：p=0.892；性别：p=0.512,)，而异常ATXN3等位基因的CAG重复数、正常ATXN3等位基因的CAG重复数及两者的相互作用对患者的发病年龄有显著影响（异常等位基因的CAG重复数：p=0.000；正常等位基因的CAG重复数：p=0.043；两者的相互作用：p=0.035）。相较只含异常等位基因的CAG重复数的线性回归模型，能增加MJD患者发病年龄变异性额外0.7％的解释作用。 5.262例已知遗传方式的MJD患者中，父系遗传患者与母系遗传患者的发病年龄存在显著性的统计学差异(33.5±0.833vs36.6±1.022,p=0.021)，但在调整异常扩增的CAG重复数之后，这种显著性统计学差异消失（(ANCOVA, F=0.043, p=0.835)。 6.纯合MJD患者的ATXN3基因的CAG重复次数为60/60,较具有相同CAG重复数的杂合MJD患者的发病年龄明显提前,且病情进展更快。结论： 1.异常ATXN3等位基因的CAG重复数与MJD患者发病年龄呈负相关，能解释65.9%的发病年龄变异性。因此不能作为MJD患者发病年龄的独立预测因子 2. APOE基因多态性与MJD患者发病年龄不相关，且性别不影响MJD患者的发病年龄。 3.正常ATXN3等位基因的CAG重复数、异常ATXN3等位基因的CAG重复数及两者的相互作用会影响MJD患者的发病年龄。 4.遗传方式会影响患者异常ATXN3的CAG重复数，父系遗传患者的异常CAG重复数大于母系遗传患者的CAG重复数。 5.遗传方式与MJD患者发病年龄变异性相关。 6.纯合的MJD患者中相较于杂合患者，其发病年龄显著性提早且病程进展更为迅速。
[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 卤0.56 10-72 years old. The average CAG repeats of the ATXN3 alleles were 75.90 卤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 卤0.833vs36.6 卤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.
【学位授予单位】：福建医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R744.7

【相似文献】