GEMIN4 Variants: Risk Profiling, Bioinformatics, and Dynamic Simulations Uncover Susceptibility to Bladder Carcinoma

IF 4.7 3区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Archives of Medical Research Pub Date : 2024-02-23 DOI:10.1016/j.arcmed.2024.102970

Abdallah S. Mohamed , Afrah F. Salama , Magdy A. Sabaa , Eman Toraih , Rami M. Elshazli

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Abstract

Background

The relationship between GEMIN4 genetic variants and cancer, especially bladder carcinoma (BLCA), has been explored without conclusive results. This study aims to elucidate the link between GEMIN4 polymorphisms and BLCA susceptibility through genetic analyses, bioinformatics, and molecular dynamics (MD) simulations.

Methods

A cohort of 249 participants (121 BLCA patients and 128 unrelated controls) was enrolled. PCR was employed for allelic discrimination of GEMIN4 variants, followed by subgroup stratification, haplotype analyses, structural prediction using the AlphaFold2 prediction tool, subsequent MD simulations, structural analysis, and residue interaction mapping using Desmond, UCSF ChimeraX, and Cytoscape softwares.

Results

The rs.2740348*G variant demonstrated a protective role against BLCA in allelic (OR = 0.55, p = 0.002) and recessive (OR = 0.54, p = 0.017) models, whereas the rs.7813*T variant increased BLCA risk under the recessive model (OR = 1.90, p = 0.019). Haplotype analysis revealed a significant association between GEMIN4 haplotype (rs.2740348*C/rs.7813*T) with increased BLCA risk (OR = 2.01, p = 0.004). Univariate analysis revealed associations of the variants with albumin levels and absolute neutrophil count in BLCA patients. Pathogenicity evaluation categorized p.Gln450Glu as neutral and p.Arg1033Cys as deleterious. MD simulations revealed structural alterations and conformational shifts in the GEMIN4 protein induced by the Glu450 and Cys1033 mutations.

Conclusions

The study highlights the dual role of GEMIN4 variants in BLCA susceptibility, with rs.2740348 conferring protection and rs.7813 increasing risk. The Glu450 residue positively impacted protein stability, while Cys1033 had a detrimental effect on protein function. These findings underscore the significance of GEMIN4 variants in BLCA susceptibility and pave the way for future diagnostic and therapeutic initiatives.

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GEMIN4 变异：风险分析、生物信息学和动态模拟揭示了膀胱癌的易感性

背景GEMIN4基因变异与癌症，尤其是膀胱癌（BLCA）之间的关系已被探讨过，但没有得出结论。本研究旨在通过基因分析、生物信息学和分子动力学（MD）模拟，阐明 GEMIN4 多态性与膀胱癌易感性之间的联系。采用 PCR 对 GEMIN4 变体进行等位基因鉴别，然后进行亚组分层、单体型分析、使用 AlphaFold2 预测工具进行结构预测、随后使用 Desmond、UCSF ChimeraX 和 Cytoscape 软件进行 MD 模拟、结构分析和残基相互作用绘图。*G变异在等位（OR = 0.55，p = 0.002）和隐性（OR = 0.54，p = 0.017）模型中对BLCA具有保护作用，而在隐性模型中，rs.7813*T变异会增加BLCA风险（OR = 1.90，p = 0.019）。单倍型分析显示，GEMIN4 单倍型（rs.2740348*C/rs.7813*T）与 BLCA 风险增加有显著关联（OR = 2.01，p = 0.004）。单变量分析显示，这些变异与 BLCA 患者的白蛋白水平和中性粒细胞绝对计数有关。致病性评估将p.Gln450Glu归为中性，p.Arg1033Cys归为有害。MD 模拟显示了 Glu450 和 Cys1033 突变诱导的 GEMIN4 蛋白的结构改变和构象转变。结论该研究强调了 GEMIN4 变体在 BLCA 易感性中的双重作用，rs.2740348 具有保护作用，而 rs.7813 则增加了风险。Glu450残基对蛋白质稳定性有积极影响，而Cys1033则对蛋白质功能有不利影响。这些发现强调了 GEMIN4 变异在 BLCA 易感性中的重要性，并为未来的诊断和治疗措施铺平了道路。

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来源期刊

Archives of Medical Research 医学-医学：研究与实验

CiteScore

12.50

自引率

0.00%

发文量

审稿时长

28 days

期刊介绍： Archives of Medical Research serves as a platform for publishing original peer-reviewed medical research, aiming to bridge gaps created by medical specialization. The journal covers three main categories - biomedical, clinical, and epidemiological contributions, along with review articles and preliminary communications. With an international scope, it presents the study of diseases from diverse perspectives, offering the medical community original investigations ranging from molecular biology to clinical epidemiology in a single publication.