摘要
在中枢神经系统,Hsp70s对修复和清除被应力破坏的细胞内蛋白质有着保护作用。当然,HSP70对阿尔茨海默病也有保护作用。 HSP70-1 +190 G/C的多态性位在基因的5''非翻译区并且和转录结合因子的改变有关。HSP70-2 +1267 A/G会导致编码区的突变并影响mRNA 翻译的机制。在编码区,HSP70-hom +2437 A/G 使Met 替换成 The (M493T) ,影响与底物的结合从而影响hsp70分子伴侣蛋白的活性。 考虑到我们之前对HLAⅢ类区域的研究,本文研究目的是探讨阿尔茨海默病对HSP70基因多态性的敏感性,以及基于RAGE、HSP70和 TNF三种基因的变异,对HLAⅢ类单倍型结构的作用提供一个假说。我们利用PCR-RFLP 和 PCR-TSP研究了这其多态性。 我们对173 个AD患者以及211个正常对照组进行研究。与对照组相比(C等位基因:P 值 = 0.018,G等位基因:p 值 = 0.02),AD患者HSP70-1 +190 G/C中C等位基因的分布频率显著降低。本文聚焦于单体型重建。与控制组相比(经验p值=0.007),我们观察到AD患者中GGT单倍型频率(经验p值=0.0133)显著降低,而GAT 单倍型频率有所升高。总HLAⅢ类单倍型得到重建。致病单倍型是以下的几种: TTGATGGG ( p值 =0,005; 经验p值 =0.0042); TTGATAGG (p值 =0,45; 经验p值 =0.034)。与具有TTGGTGGG (p 值=0.0138; 经验p 值=0.0102); TTCGTGGG (p 值=0.021;经验p 值=0.017); TTCGTGGA (p 值 =0.058; 经验p 值 =0.043)单倍型相比,具有治病单倍型的患者可能会较早的发病。 RAGE 、 TNF和 HSP70变异引起的单倍型整体变化影响的AD表型 (综合性LR检测p值=0.00185)的存在形式。在调整整体型(限制性 LR 检测p值=0.0114 ,p值=0.0044)的影响后,HSP701 和HSP702能独立影响患AD的风险。这些数据证明了HLA class III类与A有关。
关键词: 阿尔茨海默病,HLAIII类,单倍型, HS70 单体,氧化应激,神经退行性疾病。
Current Alzheimer Research
Title:The Possible Involvement of HLA Class III Haplotype (RAGE, HSP70 and TNF Genes) in Alzheimer's Disease
Volume: 12 Issue: 10
Author(s): Chiara Boiocchi, Elisa Maggioli, Maria Cristina Monti, Michele Zorzetto, Elena Sinforiani, Cristina Cereda and Giovanni Ricevuti and Mariaclara Cuccia
Affiliation:
关键词: 阿尔茨海默病,HLAIII类,单倍型, HS70 单体,氧化应激,神经退行性疾病。
摘要: In the central nervous system Hsp70s seems to have a protective role in repair and removal of cellular proteins damaged by stress conditions. A protective role of Hsp70 was also shown in Alzheimer Disease.
The HSP70-1 +190 G/C polymorphism is located in the gene 5’UTR region and it is implicated in alteration of the transcription binding factor; HSP70-2 +1267 A/G causes a silent mutation in the coding region and it seems to influence the mechanism of mRNA translation; HSP70-hom +2437 A/G causes a substitution Met → The (M493T) in the coding region and it seems to influence the bond with the substrate and therefore on the chaperone activity of hsp70.
The aim of our study will be to investigate Alzheimer susceptibility to Hsp70 polymorphisms, taking into account our previous findings on HLA class III region, and to hypothesize a role of HLA class III haplotype configuration based on the variants of three genes: RAGE, HSP70 and TNF. We studied these polymorphisms with PCR-RFLP and PCR-TSP.
We investigated 173 AD patients and 211 control subjects. Our results have shown a statistically significant decrease of the C allele frequency of the HSP70-1 +190 G/C polymorphism in AD patients vs controls (P value = 0,018), as well as the G allele of HSP70-2 +1267 G/A (p value = 0,02). We focalized our attention on haplotype reconstruction. We have observed a significant statistically decrease of GGT haplotype frequency (empirical p-value=0.0133 ); GAT haplotype was statistically significant increase in AD patients compared with control (empirical p-value=0.007). The total HLA class III haplotype are reconstructed. The causative haplotypes are the following ones: TTGATGGG ( p value =0,005; empirical p =0,0042); TTGATAGG (p value =0,45; empirical p =0,034). Patients with these haplotypes may show an earlier onset of the disease than patients with TTGGTGGG (p value=0,0138; empirical p =0,0102); TTCGTGGG (p value=0,021; empirical p =0,017); TTCGTGGA (p value =0,058; empirical p =0,043) haplotypes. The overall variation of the haplotypes formed by the RAGE and TNF and HSP70 variants influenced the presence of the AD phenotype (omnibus association LR test p-value 0.00185), HSP701 and HSP702 showed independent effect on AD risk after adjusting for the effect of the entire haplotype (conditional LR test p-value=0.0114 and p-value=0.0044 respectively). These data confirm the involvement of HLA class III in AD.
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Chiara Boiocchi, Elisa Maggioli, Maria Cristina Monti, Michele Zorzetto, Elena Sinforiani, Cristina Cereda and Giovanni Ricevuti and Mariaclara Cuccia , The Possible Involvement of HLA Class III Haplotype (RAGE, HSP70 and TNF Genes) in Alzheimer's Disease, Current Alzheimer Research 2015; 12 (10) . https://dx.doi.org/10.2174/1567205012666151027130635
DOI https://dx.doi.org/10.2174/1567205012666151027130635 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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