Polymorphism in Genes Encoding HSP40 Family Proteins is Associated with Ischemic Stroke Risk and Brain Infarct Size: A Pilot Study.

IF 2.5 4区医学 Q3 NEUROSCIENCES

Journal of integrative neuroscience Pub Date : 2024-12-04 DOI:10.31083/j.jin2312211

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

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引用次数: 0

Abstract

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 (DNAJB1, DNAJB2, DNAJA1, DNAJA2, DNAJA3 and DNAJC7) 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 DNAJA2 decreased the risk of IS exclusively in male patients (odds ratio = 0.81, 95% confidence interval 0.78-0.98, p = 0.028); rs7189628 DNAJA2 increased the brain infarct size (p = 0.04); and rs6500605 DNAJA3 lowered the age of onset of IS (p = 0.03). SNPs rs10448231 DNAJA1, rs7189628 DNAJA2, rs4926222 DNAJB1 and rs2034598 DNAJA2 were involved in the strongest epistatic interactions linked to IS; SNP rs10448231 DNAJA1 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 DNAJA2×rs4926222 DNAJB1, 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 DNAJA3, rs10448231 DNAJA1, rs2034598 DNAJA2, rs7189628 DNAJA2 and rs4926222 DNAJB1, 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 HSP40 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.

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编码HSP40家族蛋白的基因多态性与缺血性卒中风险和脑梗死大小相关：一项初步研究

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可能作用已经被揭示；然而，迄今为止，关于编码HSP40家族蛋白的基因参与IS的分子遗传学研究尚未开展。目的：我们试图确定编码HSP40家族蛋白的基因（DNAJB1、DNAJB2、DNAJA1、DNAJA2、DNAJA3和DNAJC7）的9个单核苷酸多态性（snp）是否与IS的风险和临床特征相关。方法：采用基于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 DNAJA2降低了男性患者患IS的风险（优势比= 0.81,95%可信区间0.78 ~ 0.98,p = 0.028）；rs7189628 DNAJA2增加脑梗死面积（p = 0.04）；rs6500605 DNAJA3降低IS发病年龄（p = 0.03）。snp rs10448231 DNAJA1、rs7189628 DNAJA2、rs4926222 DNAJB1和rs2034598 DNAJA2参与与IS相关的最强上位互作；SNP rs10448231 DNAJA1具有最基本的单效应（is熵的2.96%）；所有排名前几位的SNP-SNP相互作用模型都包括rs7189628 DNAJA2×rs4926222 DNAJB1的两两组合，这是决定IS易感性的关键因素。在与所研究snp的相互作用中，吸烟具有多向效应（协同效应、拮抗效应或加性效应），且单效应最强（占IS熵的3.47%），超过rs6500605 DNAJA3、rs10448231 DNAJA1、rs2034598 DNAJA2、rs7189628 DNAJA2和rs4926222 DNAJB1的单效应，参与了最佳G×E模型，决定了0.03% ~ 0.73%的IS熵。结论：我们首次发现编码HSP40家族蛋白的基因多态性是IS及其临床表现的主要危险因素。综合生物信息学分析揭示了其分子机制，强调了其在IS发病机制中的重要意义，主要反映了热应激、蛋白质平衡和细胞信号传导的调节。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of integrative neuroscience 医学-神经科学

CiteScore

2.80

自引率

5.60%

发文量

173

审稿时长

2 months

期刊介绍： JIN is an international peer-reviewed, open access journal. JIN publishes leading-edge research at the interface of theoretical and experimental neuroscience, focusing across hierarchical levels of brain organization to better understand how diverse functions are integrated. We encourage submissions from scientists of all specialties that relate to brain functioning.