He Lu, Lin Suzhen, Pan Hong, Shen Ruinan, Wang Mengyan, Liu Zhihao, Sun Shiyao, Tan Yuyan, Wang Ying, Chen Shengdi, Ding Jianqing
Department of Neurology, Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Laboratory of Neurodegenerative Diseases, Institute of Health Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Aging Neurosci. 2019 Feb 26;11:24. doi: 10.3389/fnagi.2019.00024. eCollection 2019.
Low DJ-1 protein level caused by DJ-1 gene mutation leads to autosomal recessive Parkinson's disease (PD) due to impaired antioxidative activity. In sporadic PD patients, although mutations were rarely found, lower DJ-1 protein level was also reported. Dysregulation of DJ-1 gene expression might contribute to low DJ-1 protein level. Since the promoter is the most important element to initiate gene expression, whether polymorphisms in the DJ-1 promoter result in the dysregulation of gene expression, thus leading to low protein level and causing PD, is worth exploring. The DJ-1 promoter region was sequenced in a Chinese cohort to evaluate possible links between DJ-1 promoter polymorphisms, PD risk and clinical phenotypes. Dual-luciferase reporter assay was conducted to evaluate the influence of promoter polymorphisms on DJ-1 transcriptional activity. Related information in an existing genome-wide association studies (GWAS) database were looked up, meta-analysis of the present study and other previous reports was conducted, and expression quantitative trait loci (eQTL) analysis was performed to further explore the association. Three single nucleotide polymorphisms (SNPs) (rs17523802, rs226249, and rs35675666) and one 18 bp deletion (rs200968609) were observed in our cohort. However, there was no significant association between the four detected genetic variations and the risk of PD either in allelic or genotype model, in single-point analysis or haplotype analysis. This was supported by the meta-analysis of this study and previous reports as well as that of GWAS database PDGene. Dual luciferase reporter assay suggested these promoter polymorphisms had no influence on DJ-1 transcriptive activity, which is consistent with the eQTL analysis results using the data from GTEx database. Thus, DJ-1 promoter polymorphisms may play little role in the dysregulation of DJ-1 expression and PD susceptibility in sporadic PD.
DJ-1基因突变导致DJ-1蛋白水平降低，由于抗氧化活性受损，进而引发常染色体隐性帕金森病（PD）。在散发性PD患者中，虽然很少发现突变，但也有报道称DJ-1蛋白水平较低。DJ-1基因表达失调可能导致DJ-1蛋白水平降低。由于启动子是启动基因表达的最重要元件，DJ-1启动子多态性是否会导致基因表达失调，进而导致蛋白水平降低并引发PD，值得探讨。对一个中国队列的DJ-1启动子区域进行测序，以评估DJ-1启动子多态性、PD风险和临床表型之间的可能联系。进行双荧光素酶报告基因检测，以评估启动子多态性对DJ-1转录活性的影响。查阅现有全基因组关联研究（GWAS）数据库中的相关信息，对本研究和其他先前报告进行荟萃分析，并进行表达定量性状位点（eQTL）分析以进一步探讨关联性。在我们的队列中观察到三个单核苷酸多态性（SNP）（rs17523802、rs226249和rs35675666）和一个18 bp缺失（rs200968609）。然而，在等位基因或基因型模型中，无论是单点分析还是单倍型分析，这四个检测到的基因变异与PD风险之间均无显著关联。本研究和先前报告以及GWAS数据库PDGene的荟萃分析均支持这一结果。双荧光素酶报告基因检测表明，这些启动子多态性对DJ-1转录活性没有影响，这与使用GTEx数据库数据进行的eQTL分析结果一致。因此，DJ-1启动子多态性在散发性PD的DJ-1表达失调和PD易感性中可能作用不大。
