编码HSP40家族蛋白的基因多态性与缺血性中风风险及脑梗死大小相关：一项初步研究。

Kobzeva Ksenia A, Gurtovoy Denis E, Polonikov Alexey V, Pokrovsky Vladimir M, Patrakhanov Evgeny A, Bushueva Olga Y

Laboratory of Genomic Research, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia.

Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 305041 Kursk, Russia.

J Integr Neurosci. 2024 Dec 4;23(12):211. doi: 10.31083/j.jin2312211.

BACKGROUND

Heat shock proteins (HSPs) play a critical role in the molecular mechanisms of ischemic stroke (IS). A possible role for HSP40 family proteins in atherosclerosis progression has already been revealed; however, to date, molecular genetic studies on the involvement of genes encoding proteins of the HSP40 family in IS have not yet been carried out.

AIM

We sought to determine whether nine single nucleotide polymorphisms (SNPs) in genes encoding HSP40 family proteins (, , , , and ) are associated with the risk and clinical features of IS.

METHODS

Using TaqMan-based polymerase chain reaction (PCR) and the MassArray-4 system, DNA samples of 2551 Russians - 1306 IS patients and 1245 healthy individuals - were genotyped.

RESULTS

SNP rs2034598 decreased the risk of IS exclusively in male patients (odds ratio = 0.81, 95% confidence interval 0.78-0.98, = 0.028); rs7189628 increased the brain infarct size ( = 0.04); and rs6500605 lowered the age of onset of IS ( = 0.03). SNPs rs10448231 , rs7189628 , rs4926222 and rs2034598 were involved in the strongest epistatic interactions linked to IS; SNP rs10448231 is characterised by the most essential mono-effect (2.96% of IS entropy); all of the top SNP-SNP interaction models included the pairwise combination rs7189628 ×rs4926222 , which was found to be a key factor determining susceptibility to IS. In interactions with the studied SNPs, smoking was found to have multidirectional effects (synergism, antagonism or additive effect) and the strongest mono-effect (3.47% of IS entropy), exceeding the mono-effects of rs6500605 , rs10448231 , rs2034598 , rs7189628 and rs4926222 , involved in the best G×E models and determining 0.03%-0.73% of IS entropy.

CONCLUSIONS

We are the first to discover polymorphisms in genes encoding family proteins as a major risk factor for IS and its clinical manifestations. The comprehensive bioinformatics analysis revealed molecular mechanisms, underscoring their significance in the pathogenesis of IS, primarily reflecting the regulation of heat stress, proteostasis and cellular signalling.

背景

热休克蛋白（HSPs）在缺血性脑卒中（IS）的分子机制中起关键作用。HSP40家族蛋白在动脉粥样硬化进展中的潜在作用已被揭示；然而，迄今为止，尚未开展关于编码HSP40家族蛋白的基因参与IS的分子遗传学研究。

目的

我们试图确定编码HSP40家族蛋白的基因中的九个单核苷酸多态性（SNPs）（、、、、、、、、）是否与IS的风险及临床特征相关。

方法

使用基于TaqMan的聚合酶链反应（PCR）和MassArray-4系统，对2551名俄罗斯人（1306名IS患者和1245名健康个体）的DNA样本进行基因分型。

结果

SNP rs2034598 仅在男性患者中降低了IS风险（优势比=0.81，95%置信区间0.78 - 0.98， =0.028）；rs7189628 增加了脑梗死面积（ =0.04）；rs6500605 降低了IS的发病年龄（ =0.03）。SNP rs10448231 、rs7189628 、rs4926222 和rs2034598 参与了与IS相关的最强上位相互作用；SNP rs10448231 具有最显著的单效应（占IS熵的2.96%）；所有顶级SNP - SNP相互作用模型均包括成对组合rs7189628 ×rs4926222 ，该组合被发现是决定IS易感性的关键因素。在与所研究的SNPs相互作用中，发现吸烟具有多向效应（协同、拮抗或加性效应）且单效应最强（占IS熵的3.47%），超过了参与最佳基因-环境（G×E）模型且决定0.03% - 0.73%的IS熵的rs6500605 、rs10448231 、rs2034598 、rs7189628 和rs4926222 的单效应。