GRIN2A polymorphisms and expression levels are associated with lead-induced neurotoxicity
GRIN2A polymorphisms and expression levels are associated with lead-induced neurotoxicity
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DOI：
10.1177/0748233716647636
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发表时间：
2017-04-01
影响因子：
1.9
通讯作者：
Li, Chunping
中科院分区：
文献类型：
--
作者：
Wu, Yu;Wang, Yiqing;Li, Chunping
铅是N-甲基-D-天冬氨酸受体（NMDAR）的拮抗剂。GRIN 2A编码NMDARs的一个重要亚基，可能是铅神经毒性机制中的一个关键因素。GRIN 2A表达水平或基因变异的变化可能是铅诱导神经毒性的机制。在这项研究中，我们假设GRIN 2A可能有助于铅诱导的神经毒性。进行初步HEK 293细胞实验以分析GRIN 2A表达与铅暴露之间的关联。此外，在一项基于人群的研究中，在铅暴露人群和对照人群中测量了血清GRIN 2A水平。为进一步探讨GRIN 2A基因单核苷酸多态性（SNP）在铅致神经毒性中的作用，对399名铅暴露者和398名对照者的3个标签SNP（rs 2650429、rs6497540和rs 9302415）进行了基因分型。与无铅细胞相比，铅暴露降低HEK 293细胞中GRIN 2A表达水平（p < 0.001）。与对照组相比，铅暴露者血清GRIN 2A水平较低（p < 0.001），并且我们发现GRIN 2A水平随着血铅水平的升高而降低（p < 0.001）。此外，我们发现rs 2650429 CT和TT基因型与铅中毒风险之间的显著相关性，与rs 2650429 CC基因型相比（校正比值比= 1.42，95%置信区间= 1.01-2.00）。因此，GRIN 2A表达水平和变体的变化可能是铅诱导神经毒性发展的重要机制。
Lead acts as an antagonist of the N-methyl-D-aspartate receptor (NMDAR). GRIN2A encodes an important subunit of NMDARs and may be a critical factor in the mechanism of lead neurotoxicity. Changes in GRIN2A expression levels or gene variants may be mechanisms of lead-induced neurotoxicity. In this study, we hypothesized that GRIN2A might contribute to lead-induced neurotoxicity. A preliminary HEK293 cell experiment was performed to analyze the association between GRIN2A expression and lead exposure. In addition, in a population-based study, serum GRIN2A levels were measured in both lead-exposed and control populations. To detect further the influence of GRIN2A gene single nucleotide polymorphisms (SNPs) in leadinduced neurotoxicity, 3 tag SNPs (rs2650429, rs6497540, and rs9302415) were genotyped in a case-control study that included 399 lead-exposed subjects and 398 controls. Lead exposure decreased GRIN2A expression levels in HEK293 cells (p < 0.001) compared with lead-free cells. Lead-exposed individuals had lower serum GRIN2A levels compared with controls (p < 0.001), and we found a trend of decreasing GRIN2A level with an increase in blood lead level (p < 0.001). In addition, we found a significant association between rs2650429 CT and TT genotypes and risk of lead poisoning compared with the rs2650429 CC genotype (adjusted odds ratio = 1.42, 95% confidence interval = 1.01-2.00]. Therefore, changes in GRIN2A expression levels and variants may be important mechanisms in the development of lead-induced neurotoxicity.