Abdallah S. Mohamed , Afrah F. Salama , Magdy A. Sabaa , Eman Toraih , Rami M. Elshazli
{"title":"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","authors":"Abdallah S. Mohamed , Afrah F. Salama , Magdy A. Sabaa , Eman Toraih , Rami M. Elshazli","doi":"10.1016/j.arcmed.2024.102970","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>The rs.2740348*G variant demonstrated a protective role against BLCA in allelic (OR = 0.55, <em>p</em> = 0.002) and recessive (OR = 0.54, <em>p</em> = 0.017) models, whereas the rs.7813*T variant increased BLCA risk under the recessive model (OR = 1.90, <em>p</em> = 0.019). Haplotype analysis revealed a significant association between GEMIN4 haplotype (rs.2740348*C/rs.7813*T) with increased BLCA risk (OR = 2.01, <em>p</em> = 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.</p></div><div><h3>Conclusions</h3><p>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.</p></div>","PeriodicalId":8318,"journal":{"name":"Archives of Medical Research","volume":"55 3","pages":"Article 102970"},"PeriodicalIF":4.7000,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0188440924000237/pdfft?md5=eceb7a893ea57109bcba414cf6da3e02&pid=1-s2.0-S0188440924000237-main.pdf","citationCount":"0","resultStr":"{\"title\":\"GEMIN4 Variants: Risk Profiling, Bioinformatics, and Dynamic Simulations Uncover Susceptibility to Bladder Carcinoma\",\"authors\":\"Abdallah S. Mohamed , Afrah F. Salama , Magdy A. Sabaa , Eman Toraih , Rami M. Elshazli\",\"doi\":\"10.1016/j.arcmed.2024.102970\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>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.</p></div><div><h3>Methods</h3><p>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.</p></div><div><h3>Results</h3><p>The rs.2740348*G variant demonstrated a protective role against BLCA in allelic (OR = 0.55, <em>p</em> = 0.002) and recessive (OR = 0.54, <em>p</em> = 0.017) models, whereas the rs.7813*T variant increased BLCA risk under the recessive model (OR = 1.90, <em>p</em> = 0.019). Haplotype analysis revealed a significant association between GEMIN4 haplotype (rs.2740348*C/rs.7813*T) with increased BLCA risk (OR = 2.01, <em>p</em> = 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.</p></div><div><h3>Conclusions</h3><p>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.</p></div>\",\"PeriodicalId\":8318,\"journal\":{\"name\":\"Archives of Medical Research\",\"volume\":\"55 3\",\"pages\":\"Article 102970\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2024-02-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0188440924000237/pdfft?md5=eceb7a893ea57109bcba414cf6da3e02&pid=1-s2.0-S0188440924000237-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Archives of Medical Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0188440924000237\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Medical Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0188440924000237","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
GEMIN4 Variants: Risk Profiling, Bioinformatics, and Dynamic Simulations Uncover Susceptibility to Bladder Carcinoma
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.
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.
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