von Otter Malin, Bergström Petra, Quattrone Aldo, De Marco Elvira Valeria, Annesi Grazia, Söderkvist Peter, Wettinger Stephanie Bezzina, Drozdzik Marek, Bialecka Monika, Nissbrandt Hans, Klein Christine, Nilsson Michael, Hammarsten Ola, Nilsson Staffan, Zetterberg Henrik
BMC Med Genet. 2014 Dec 12;15:131. doi: 10.1186/s12881-014-0131-4.
The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson's disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson's disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson's disease in meta-analyses including all six materials.
Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson's disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson's disease were investigated in each material individually and in meta-analyses of the obtained results.
Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+1.1 years per allele, p = 0.048) of Parkinson's disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson's disease (rs7557529 G > A, -1.0 years per allele, p = 0.042; rs35652124 A > G, -1.1 years per allele, p = 0.045; rs2886161 A > G, -1.2 years per allele, p = 0.021; rs1806649 G > A, +1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson's disease.
Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson's disease. Functional studies are now needed to explore these results further.
由NFE2L2基因编码的转录因子Nrf2是细胞抵御氧化应激的重要调节因子。帕金森病是一种与氧化应激高度相关的神经退行性疾病。在之前发表的一项研究中，我们报道了在瑞典的发现材料和波兰的重复材料中，NFE2L2单倍型与特发性帕金森病的风险及发病年龄之间的关联。在此，我们扩展了重复研究，并进行了荟萃分析，纳入了波兰材料以及四个新的独立欧洲患者-对照材料。此外，在包括所有六个材料的荟萃分析中，对单倍型窗口内包含的所有单核苷酸多态性（SNP）进行了单独研究，以探讨其与帕金森病的关联。
共研究了1038例患者和1600例对照受试者。基于之前NFE2L2单倍型与帕金森病的关联，通过等位基因鉴别对五个NFE2L2标签SNP进行基因分型，并通过测序对三个功能性NFE2L2启动子SNP进行基因分型。在每个材料中分别以及对所得结果进行荟萃分析时，研究了各个SNP和单倍型对帕金森病风险及发病年龄的影响。
NFE2L2单倍型的荟萃分析显示，单倍型GAGCAAAA（包括功能完全的启动子单倍型AGC）与帕金森病风险降低（每个等位基因的比值比[OR]=0.8，p=0.012）和发病延迟（每个等位基因+1.1年，p=0.048）相关。这些结果支持了第一项研究中先前观察到的该单倍型的保护作用。此外，对单倍型中包含的SNP进行的荟萃分析揭示了四个与帕金森病发病年龄相关的NFE2L2 SNP（rs7557529 G>A，每个等位基因-1.0年，p=0.042；rs35652124 A>G，每个等位基因-1.1年，p=0.045；rs2886161 A>G，每个等位基因-1.2年，p=0.021；rs1806649 G>A，每个等位基因+1.2年，p=0.029）。其中一个（rs35652124）是位于NFE2L2启动子中的功能性SNP。没有单个SNP与帕金森病风险相关。
我们的结果支持以下假设，即编码细胞抵御氧化应激核心蛋白的NFE2L2基因变异可能参与帕金森病的发病机制。现在需要进行功能研究以进一步探索这些结果。
