【作者】 王莹；

【导师】 谢安木；

【作者基本信息】 青岛大学 ， 神经病学， 2022， 硕士

【摘要】 目的:越来越多的证据表明溶酶体途径功能障碍与帕金森病(Parkinson’s disease,PD)的发病机制密切相关。考虑到分拣蛋白相关受体1(sortilin-related receptor 1,SORL1)与溶酶体功能障碍、神经退行性疾病(尤其是PD)中错误折叠蛋白的异常聚集关系密切,并且胶质细胞源性神经营养因子(glial cell-derived neurotrophic factor,GDNF)是影响多巴胺系统活性的最有效神经营养因子,而SORL1可能通过影响上述途径来诱发PD,我们研究了SORL1基因的三个位点(rs1010159、rs1629493和rs2298813)多态性与中国北方人PD风险之间的相关性。方法:通过聚合酶链反应限制性片段长度多态性(polymerase chain reactions-restriction fragment length polymorphism,PCR-RFLP)对400名PD患者和400名年龄和性别匹配的健康对照者的外周血DNA进行SORL1基因的三个单核苷酸多态性(single nucleotide polymorphisms,SNP)(rs1010159、rs1629493和rs2298813)的基因分型。采用卡方检验来分析PD患者和健康对照组之间的基因型和等位基因多态性频率的统计差异。逻辑回归分析被用来计算比值比(odds ratios,ORs)和95%置信区间(95%confidence intervals,95%CIs),以评估潜在相关性。结果:PD患者rs1010159的T等位基因和rs2298813的A等位基因频率均显著高于对照组(P值分别为0.001,0.014)。对于rs1010159,亚组分析显示所有亚组中T等位基因的频率均有统计学差异(P=0.021,P=0.036,P=0.001,P=0.001,P=0.001,P=0.030);然而,基因型频率分布仅在男性PD患者与匹配的健康男性对照之间(P=0.001),以及早发性PD(early-onset PD,EOPD)与晚发性PD(late-onset PD,LOPD)与对照之间(P=0.001,P=0.001)具有统计学意义。对于rs2298813,显性模型显示,与GG基因型相比,GA+AA基因型的PD风险增加(P=0.020,OR=1.518,95%CI=1.065-2.162),基因型频率分析显示,与GG基因型相比,GA也与PD风险增加趋势相关(P=0.037,OR=1.475,95%CI=1.024-2.125),对于LOPD,其等位基因频率与匹配健康组有显著差异(P=0.017)。未发现rs1629493与PD风险之间存在明显相关性。GAT单倍型和AGT单倍型与PD易感性相关。结论:SORL1基因的rs1010159和rs2298813多态性与中国北方人群的PD易感性有关,且rs1010159的T等位基因与rs2298813的A等位基因可能均为PD发病的危险因素,而rs1629493的多态性与之无关。要了解SORL1基因与帕金森病发病机制之间的深层次的联系,需要在不同种族和更大的人群中进行更进一步的研究。更多还原

【Abstract】 Objective: There is increasing evidence that lysosomal pathway dysfunction is closely linked to the pathogenesis of Parkinson’s disease(PD).Considering the relationship between sortilin-related receptor 1(SORL1)and lysosomal dysfunction,the abnormal aggregation of misfolded proteins in neurodegenerative disorders,especially in PD,and that glial cell-derived neurotrophic factor(GDNF)is the most effective neurotrophic factor affecting the activity of the dopamine system,and that SORL1 may induce PD by affecting the above ways,we investigated the correlation between three genetic variants(rs1010159,rs1629493,and rs2298813)of SORL1 gene polymorphisms and the risk of PD in the northern Chinese population.Methods: Three single-nucleotide polymorphisms(SNP)of SORL1 genes(rs1010159,rs1629493,and rs2298813)were genotyped by polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP)on the DNA of 400 patients with PD and400 healthy controls matched by age and gender.The chi-square test was used to analyze the statistical differences in genotypic and allelic polymorphism frequency between PD patients and healthy controls.Logistic regression analysis was used to calculate odds ratios(ORs)and 95% confidence intervals(CIs)to estimate potential correlations.Results: The frequencies of the T allele of rs1010159 and the A allele of rs2298813 in patients with PD were much higher than those in the controls(P=0.001,P= 0.014,respectively).For rs1010159,subgroup analysis showed statistical changes in the frequency of the T allele in all subgroups(P=0.021,P =0.036,P=0.001,P=0.001,P=0.001,P=0.030,respectively);however,genotypic frequency distributions were statistically significant only between male patients with PD and matched healthy male controls(P=0.001),and between early-onset PD(EOPD)and late-onset PD(LOPD)and controls(P=0.001,P=0.001).For rs2298813,the explicit model showed that the GA+AA genotype had an increased risk of PD compared with the GG genotype(P =0.020,OR=1.518,95% CI=1.065-2.162),and the additive model showed that GA was also associated with a higher trend in PD compared with the GG genotype(P=0.037,OR=1.475,95% CI =1.024-2.125),and the allelic frequencies of the LOPD was statistically different from the matched healthy group(P=0.017).No distinct correlation was found between rs1629493 and PD risk.The GAT haplotype,together with the AGT haplotype,was associated with PD susceptibility.Conclusions: The rs1010159 and rs2298813 polymorphisms of the SORL1 gene are associated with PD susceptibility in northern China,and both the T allele of rs1010159 and the A allele of rs2298813 may both be risk factors for PD,but the polymorphism of rs1629493 is not.Studies in different ethnicities and larger populations are indispensable for understanding the intrinsic correlation between the SORL1 gene and PD pathogenesis.更多还原