Human Gene最新文献_第10页

βS haplotypes: Genetic profile and association with biochemical parameters in individuals with Sickle cell anemia in Western Bahia, Brazil βS单倍型：巴西西巴伊亚镰状细胞性贫血患者的遗传特征及其与生化参数的关系

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-18 DOI: 10.1016/j.humgen.2025.201438

Ilana Luize Rocha Santana , Raphael Magalhães , Victoria Simões Bernardo , Manoel Ferreira de Magalhães Filho , Pâmela Lourdes Pereira da Silva , Larissa Paola Rodrigues Venancio

Sickle cell anemia (SCA) is a hemoglobinopathy with a heterogeneous clinical presentation that, in part, results from complex interactions between genetic factors, some of which are explained by haplotypes in the β-globin (β^S) gene cluster. This study identified the main haplotypic profiles of individuals with SCA in Western Bahia, Brazil, and evaluates the possible relationship between the genetic profile associated with haplotype inheritance and clinical follow-up parameters presented by the individuals participating in the study. The Bantu/Benin genotype was more frequent, although it did not show a statistically significant difference compared to the Bantu/Bantu genotype. As described in other locations in Brazil, the Bantu chromosome was the most frequent in this study (59 %), which supports the data on the formation and dynamics of the population concerning the geographical origin of the enslaved Africans trafficked to the capital of Western Bahia. Important hematological parameters, such as HbF, biochemical parameters associated with the hemolysis process, and phenotype severity, such as lactate dehydrogenase, aspartate aminostransferase, and direct bilirubin, were related to the Bantu/Bantu genotype. HbF levels were 4× lower, and biochemical parameters were up to 2.5× higher in Bantu/Bantu individuals who did not use hydroxycarbamide (HC) compared to carriers of the Bantu/Bantu genotype who used HC. The results indicate the importance of assessing the inheritance of β^S-haplotypes to help understand the phenotype and the relevance of HC use in the context of SCA.

镰状细胞性贫血（SCA）是一种具有异质临床表现的血红蛋白病，其部分原因是遗传因素之间复杂的相互作用，其中一些可以用β-珠蛋白（βS）基因簇中的单倍型来解释。本研究确定了巴西西巴伊亚州SCA个体的主要单倍型谱，并评估了参与研究的个体所呈现的与单倍型遗传相关的遗传谱与临床随访参数之间的可能关系。班图/贝宁基因型更常见，尽管与班图/班图基因型相比没有统计学上的显著差异。正如在巴西其他地区所描述的那样，班图染色体在本研究中是最常见的（59%），这支持了有关人口形成和动态的数据，这些数据与贩卖到西巴伊亚首都的被奴役非洲人的地理起源有关。重要的血液学参数，如HbF，与溶血过程相关的生化参数，以及表型严重程度，如乳酸脱氢酶、天冬氨酸氨基转移酶和直接胆红素，都与班图/班图基因型有关。与使用羟脲（HC）的班图/班图基因型携带者相比，不使用羟脲（HC）的班图/班图人HbF水平低4倍，生化参数高2.5倍。结果表明，评估β s单倍型的遗传对于帮助理解SCA背景下HC使用的表型和相关性具有重要意义。

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引用次数: 0

Genetic expression of NKX2-5 gene among first trimester pregnancy loss NKX2-5基因在妊娠早期流产中的表达

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-18 DOI: 10.1016/j.humgen.2025.201439

Muraleedharan Santhamma Dhanya , Selvaraj Karthick , Reba Babu Alex , Anandhi Dhanavel , Shaiju Basheer , Sreeja Sreenivasan , Rajitha Puthiya Purayil , Divakaran Dinesh Roy

First-trimester pregnancy loss is a serious public health problem, affecting both physical and mental well-being. Occurring in 10–15 % of clinically recognized pregnancies, it remains a critical issue in reproductive health. Genetic factors impacting fetal development and maternal inflammatory responses are linked to early pregnancy loss. This case-control study included 120 participants: 60 cases (including maternal samples for evaluating inflammatory markers and their products of conception or terminated fetuses without normal cardiac activity or suspected congenital heart defects for the evaluation of NKX2–5 gene expression) and 60 healthy mothers having one or two live children without any congenital heart defects as controls. Inflammatory markers CRP and IL-6 were measured using ELISA kits. Gene expression of NKX2–5 was quantified by real-time PCR after RNA extraction from products of conception or terminated fetuses, cDNA synthesis, and amplification using specific primers. Relative expression was calculated using the 2^(-ΔΔCt) method. The findings revealed significantly higher CRP and IL-6 levels in cases than controls (p < 0.001) and changes in NKX2–5 expression. The results indicate a significant increase in NKX2–5 expression in products of conception from women with early pregnancy loss compared to those with healthy pregnancies (p < 0.05). Increased maternal levels of TSH were also revealed to be an independent predictor for early abortion (OR = 3.57, p = 0.004). Our findings suggest that NKX2–5 gene deregulation and inflammation in the maternal compartment can play a role in early pregnancy loss as future candidate targets for both diagnostic and treatment intervention.

妊娠早期流产是一个严重的公共卫生问题，影响着身体和精神健康。在临床确认的怀孕中，有10 - 15%发生这种情况，它仍然是生殖健康中的一个严重问题。影响胎儿发育和母体炎症反应的遗传因素与早孕流产有关。本病例对照研究包括120名参与者：60例（包括用于评估炎症标志物及其产物的母体样本，用于评估无正常心脏活动或疑似先天性心脏缺陷的妊娠或终止胎儿，用于评估NKX2-5基因表达）和60例健康母亲，她们有一个或两个没有任何先天性心脏缺陷的活产儿作为对照。采用ELISA试剂盒检测炎症标志物CRP和IL-6。从受胎或终止胎的产物中提取RNA，合成cDNA，并使用特定引物扩增后，采用实时荧光定量PCR技术测定NKX2-5的基因表达。相对表达式采用2^（-ΔΔCt）方法计算。结果显示，病例中CRP和IL-6水平明显高于对照组(p <；0.001)和NKX2-5表达的变化。结果表明，与健康妊娠妇女相比，早期妊娠流产妇女的受精卵中NKX2-5的表达显著增加(p <；0.05)。母体TSH水平升高也是早期流产的独立预测因子（OR = 3.57, p = 0.004）。我们的研究结果表明，NKX2-5基因失调和母体间室炎症可能在早期妊娠丢失中发挥作用，作为未来诊断和治疗干预的候选目标。

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引用次数: 0

Autophagy protein 5 (ATG5) rs573775 protects Malaysian Malay women from systemic lupus erythematosus 自噬蛋白5 (ATG5) rs573775保护马来西亚马来妇女免受系统性红斑狼疮

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-16 DOI: 10.1016/j.humgen.2025.201435

Hwa Chia Chai, Kek Heng Chua

Objective

Autophagy is one of the critical cellular processes implicated in the pathogenesis of SLE. Polymorphisms in the autophagy-related genes have been associated with increased susceptibility to SLE, particularly variations in the autophagy protein 5 (ATG5) gene which has been associated with SLE in several populations. This case-control study aimed to investigate the association between polymorphisms in ATG5 and SLE in Malaysian population.

Methods

Tetra primer amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) was performed to genotype ATG5 rs6937876, rs4945747, rs573775, rs2245214 and rs548234 in 233 SLE patients and 224 healthy controls, collected from 2000 to 2015.

Results

In the overall Malaysian population, AG genotype (adjusted p = 0.013, OR = 1.327, 95 % CI: 1.040 to 1.695) of rs6937876 were significantly associated with increased SLE susceptibility. The dominant model (AG + AA) (adjusted p = 0.006, OR = 0.671, 95 % CI: 0.464 to 0.972), additive model (adjusted p = 0.005, OR = 0.462, 95 % CI: 0.291 to 0.733), and minor A allele (adjusted p = 0.007, OR = 0.628, 95 % CI: 0.447 to 0.882) of rs573775 significantly associated with Malay population by providing protection against SLE.

Conclusion

The SNPs in ATG5 seem to not only conferring SLE susceptibility to the Malaysian population but also protect them from SLE. Gene expression of these SNPs and their interactions with upstream or downstream genes and microenvironment in the Malaysian population, especially Malays, is worth further study.

目的自噬是参与SLE发病的关键细胞过程之一。自噬相关基因的多态性与SLE易感性增加有关，特别是自噬蛋白5 （ATG5）基因的变异，在一些人群中与SLE相关。本病例对照研究旨在调查马来西亚人群中ATG5多态性与SLE之间的关系。方法对2000 ~ 2015年收集的233例SLE患者和224例健康对照进行ATG5 rs6937876、rs4945747、rss573775、rs2245214和rss548234基因型分析。结果在马来西亚总体人群中，rs6937876的AG基因型（调整p = 0.013, OR = 1.327, 95% CI: 1.040 ~ 1.695）与SLE易感性增加显著相关。优势模型（AG + AA）（调整p = 0.006, OR = 0.671, 95% CI: 0.464 ~ 0.972）、加性模型（调整p = 0.005, OR = 0.462, 95% CI: 0.291 ~ 0.733）和次要A等位基因（调整p = 0.007, OR = 0.628, 95% CI: 0.447 ~ 0.882）的rs573775通过提供SLE保护与马来人群显著相关。结论ATG5的snp似乎不仅赋予马来西亚人群SLE易感性，而且保护他们免受SLE。这些snp的基因表达及其与上游或下游基因和微环境的相互作用值得进一步研究，特别是马来人。

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引用次数: 0

A study conducted in breast cancer cells found that (valproic acid) inhibits CIP2A/c-MYC/PI3K/Akt/mTOR signaling molecules and PD-L1 一项对乳腺癌细胞的研究发现，丙戊酸可抑制CIP2A/c-MYC/PI3K/Akt/mTOR信号分子和PD-L1

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-15 DOI: 10.1016/j.humgen.2025.201437

Elahe Zeinali , Vahid Bagheri , Esmaeil Rostami , Gholamreza Anani Sarab

Resistant cells significantly undermine the efficacy of breast cancer treatment. CIP2A and PD-L1 are among the major therapeutic challenges in breast cancer, as they are key drivers of drug resistance and immune evasion, respectively. Hence, identifying agents—particularly epigenetic drugs—that can suppress these factors by altering gene expression is of great interest. This study aimed to evaluate the molecular mechanisms and effects of valproic acid (VPA), a histone deacetylase inhibitor, on CIP2A and PD-L1 expression in the MCF-7 breast cancer cell line. VPA inhibited MCF-7 cell proliferation in a dose- and time-dependent manner. Treatment with VPA resulted in downregulation of CIP2A and its downstream signaling molecules c-MYC, PI3K, AKT, and mTOR. Moreover, VPA treatment reduced PD-L1 expression in MCF-7 cells. These findings suggest that VPA may offer a novel approach to addressing challenges associated with CIP2A and PD-L1. Therefore, either as a monotherapy or in combination with existing treatments, VPA could represent a promising strategy for enhancing the efficacy of breast cancer therapy.

耐药细胞显著地破坏了乳腺癌治疗的效果。CIP2A和PD-L1是乳腺癌的主要治疗挑战之一，因为它们分别是耐药和免疫逃避的关键驱动因素。因此，寻找能够通过改变基因表达来抑制这些因素的药物，尤其是表观遗传药物，是人们非常感兴趣的。本研究旨在探讨组蛋白去乙酰化酶抑制剂丙戊酸（VPA）对MCF-7乳腺癌细胞系CIP2A和PD-L1表达的影响及其分子机制。VPA抑制MCF-7细胞增殖呈剂量和时间依赖性。VPA处理导致CIP2A及其下游信号分子c-MYC、PI3K、AKT和mTOR下调。此外，VPA处理降低了MCF-7细胞中PD-L1的表达。这些发现表明，VPA可能为解决CIP2A和PD-L1相关的挑战提供了一种新的方法。因此，无论是作为单一疗法还是与现有疗法联合使用，VPA都可能是一种很有前景的提高乳腺癌治疗效果的策略。

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引用次数: 0

Systematic identification of molecular biomarkers and drug candidates targeting MAPK3 in multiple sclerosis 多发性硬化症中靶向MAPK3的分子生物标志物和候选药物的系统鉴定

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-12 DOI: 10.1016/j.humgen.2025.201436

Bilal Khan, Ruqia Sartaj, Muhammad Rahiyab, Syed Shujait Ali, Zahid Hussain, Ishaq Khan, Arshad Iqbal

Multiple sclerosis (MS) exists as a persistent autoimmune illness affecting the central nervous system because it produces demyelination and injures axons, besides causing CNS neuroinflammation. Research advances into MS pathophysiology have not solved the complexity of treating this condition. The research examined both vital MS-related molecular biomarkers as well as therapeutic possibilities through computational methods. GEO2R analyzed the gene expression dataset GSE17393, which reported that MS patients had differentially expressed genes than healthy controls. The biological processes involved in MS became clearer with the help of functional enrichment analyses, which contained both GO and KEGG pathway analysis. The STRING database enabled the construction of a PPI network, followed by hub gene identification through the CytoHubba application. The study revealed MAPK3 as the most influential hub gene essential for MS pathophysiological processes. Scientists used the Robetta server to forecast MAPK3's 3D structure, which they then optimized in Galaxy Refine before carrying out structural quality tests. Lab simulation using PyRx showed that potential medications such as Hypericin, Yibeissine, and Physalin F effectively bind with the MAPK3 protein. Among the compounds, Hypericin achieved the best binding affinity of −10.7 kcal/mol toward MAPK3, as Yibeissine and Physalin F reached −10.0 kcal/mol binding levels. MD simulations tested the stability of all MAPK3-ligand complex structures. The combination of ADME testing demonstrated that Yibeissine possessed ideal drug absorption features with strong blood-brain barrier penetration alongside good gastrointestinal absorption, yet Hypericin showed poor oral availability. The ProTox-II analysis revealed that the substance Hypericin presented major risks for mutation and cancer development, although Physalin F significantly damaged the human immune system. Current research indicates MAPK3 inhibition represents a promising treatment approach for MS, since Yibeissine stands out as the best drug candidate because it possesses an ideal ADME profile and low toxicity risks.

多发性硬化症（MS）是一种影响中枢神经系统的持续性自身免疫性疾病，除了引起中枢神经系统炎症外，还会导致脱髓鞘和轴突损伤。对多发性硬化症病理生理学的研究进展并没有解决治疗这种疾病的复杂性。该研究通过计算方法检查了重要的ms相关分子生物标志物以及治疗可能性。GEO2R分析了基因表达数据集GSE17393，该数据报告了MS患者与健康对照组的基因表达差异。在功能富集分析的帮助下，MS所涉及的生物学过程变得更加清晰，其中包括GO和KEGG途径分析。STRING数据库可以构建PPI网络，然后通过CytoHubba应用程序进行枢纽基因鉴定。该研究表明，MAPK3是MS病理生理过程中最重要的枢纽基因。科学家们使用Robetta服务器来预测MAPK3的3D结构，然后在进行结构质量测试之前，他们在Galaxy Refine中对其进行了优化。PyRx的实验室模拟显示，潜在的药物如金丝桃素（Hypericin）、益贝素（Yibeissine）和Physalin F可以有效地与MAPK3蛋白结合。其中，金丝桃素对MAPK3的结合亲合力为−10.7 kcal/mol，而益贝素和Physalin F的结合亲合力为−10.0 kcal/mol。MD模拟测试了所有mapk3配体复合物结构的稳定性。结合ADME测试表明，依贝斯辛具有理想的药物吸收特性，具有较强的血脑屏障穿透性和良好的胃肠道吸收，而金丝桃素的口服利用度较差。ProTox-II分析显示，虽然Physalin F显著损害人体免疫系统，但Hypericin物质具有突变和癌症发展的主要风险。目前的研究表明，抑制MAPK3是一种很有前途的治疗MS的方法，因为依贝昔因具有理想的ADME特征和低毒性风险，因此成为最佳候选药物。

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引用次数: 0

Investigation of lithium treatment during pregnancy on miR124 gene expression of offspring rats 妊娠期锂离子处理对子代大鼠miR124基因表达的影响

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-06 DOI: 10.1016/j.humgen.2025.201429

Zeynab Askari , Parisa Hasanein , Alishir Haidari , Seyed Mohsen Saleh , Saeedeh Askarian

Lithium, recognized as a mood stabilizer, is widely used in the treatment of bipolar disorder. Discontinuation of this medication during pregnancy can have serious consequences, leading to severe mood fluctuations such as mania or depression in the mother. Despite the advantage effects of lithium, its molecular impacts on neonates are still under investigation. The aim of this study is to examine the expression levels of the miR-124 gene in the offspring of rats whose mothers were exposed to lithium during pregnancy. In this experimental study, female rat received a daily dose of 30 mg/kg of lithium carbonate through their drinking water. The offsprings were divided into control and experimental groups and were maintained until the age of two months. The hippocampus and serum from the offspring were isolated for the analysis of target gene expression. Total RNA was extracted and cDNA was synthesized. The expression of miR-124 was estimated using qRT-PCR, using the ddCt and Pfaffl methods, and compared with the control group. The expression of miR-124 decreased in the hippocampal tissue of neonates whose mothers received lithium during pregnancy, while an increase in miR-124 expression was observed in serum samples. No significant distinction between the two evaluation methods was observed, even though the Pfaffl method claimed greater precision. The increase in miR-124 expression in serum and its decrease in hippocampal tissue may demonstrate complex changes in gene expression regulation and physiological responses, during stress, inflammation or metabolic changes. Concurrent analysis of gene expression in both tissue and serum could provide valuable insights into disease status and the body's biological responses, enabling scientists to gain a better understanding of the treatment process.

锂被认为是一种情绪稳定剂，广泛用于治疗双相情感障碍。在怀孕期间停用这种药物可能会产生严重的后果，导致母亲出现严重的情绪波动，如躁狂或抑郁。尽管锂具有优势效应，但其对新生儿的分子影响仍在研究中。本研究的目的是检测miR-124基因在怀孕期间暴露于锂的大鼠后代中的表达水平。在本实验研究中，雌性大鼠通过其饮用水每天接受30 mg/kg的碳酸锂剂量。将幼鼠分为对照组和实验组，饲养至两个月大。分离子代海马和血清进行靶基因表达分析。提取总RNA，合成cDNA。采用qRT-PCR、ddCt和Pfaffl方法估计miR-124的表达，并与对照组进行比较。母亲在怀孕期间接受锂治疗的新生儿海马组织中miR-124的表达降低，而血清样本中miR-124的表达升高。两种评估方法之间没有明显的区别，尽管Pfaffl方法声称更高的精度。在应激、炎症或代谢变化过程中，血清中miR-124表达的升高和海马组织中miR-124表达的降低可能表现出基因表达调控和生理反应的复杂变化。同时分析组织和血清中的基因表达可以为疾病状态和身体的生物反应提供有价值的见解，使科学家能够更好地了解治疗过程。

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引用次数: 0

Role of the TLR4 pathway in the development of chronic suppurative otitis media TLR4通路在慢性化脓性中耳炎发展中的作用

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-03 DOI: 10.1016/j.humgen.2025.201433

Jagadisha Tavarekere Venkataravanappa , Venkateswarlu Raavi , Sharath Balakrishna , Prasad Kothegala Chendrashekaraiah , Sridevi Prabhakara Gowda , Ashok Dhayalan , Arun Kumar Sreeramulu , Saraswathi Saraswathi , Austin Richard Surendranath

Chronic Suppurative Otitis Media (CSOM) is a debilitating chronic ear condition characterized by inflammation and infection in the middle ear. Recent research has shed light on the crucial role of Toll-Like Receptor 4 (TLR4) in mediating inflammation in CSOM and its association with disease pathogenesis. This review explores the role of the TLR4 pathway in CSOM, encompassing its gene expression, single-nucleotide polymorphisms, and inflammatory cytokines. Additionally, we discussed the role of the TLR4 pathway in other chronic inflammatory diseases, providing insights into potential therapeutic targets. While the involvement of TLR4 in CSOM and related conditions is well-documented, there remain substantial gaps in our knowledge of the underlying molecular mechanisms. This review not only highlights the current state of knowledge but also emphasizes the areas for future research in the field of otology and immunology.

慢性化脓性中耳炎（CSOM）是一种以中耳炎症和感染为特征的慢性耳部疾病。最近的研究揭示了toll样受体4 （TLR4）在介导CSOM炎症及其与疾病发病机制的关联中的关键作用。本文综述了TLR4通路在CSOM中的作用，包括其基因表达、单核苷酸多态性和炎症细胞因子。此外，我们还讨论了TLR4通路在其他慢性炎症性疾病中的作用，为潜在的治疗靶点提供了见解。虽然TLR4参与CSOM和相关疾病已被充分记录，但我们对潜在分子机制的了解仍存在实质性差距。本文综述了耳科和免疫学领域的研究现状，并对今后的研究方向进行了展望。

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引用次数: 0

Investigating molecular aspects of SARS-CoV-2 neurological manifestations, a systems biology approach 从系统生物学角度研究SARS-CoV-2神经学表现的分子方面

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-06-02 DOI: 10.1016/j.humgen.2025.201430

Maryam Mozafar , Seyed Amir Mirmotalebisohi , Ahmad Reza Shahverdi , Hakimeh Zali

Objectives

Amid the COVID-19 pandemic, reported neurological symptoms and potential syndromes such as ischemic stroke, seizure, and encephalitis highlight the neurological impact of SARS-CoV-2. We employed a systems biology approach to analyze omics transcriptional data, exploring the molecular mechanisms underlying neurological complications in COVID-19.

Methods

We retrieved post-mortem brain data of COVID-19 patients from the gene expression omnibus (GEO) dataset and constructed protein-protein interaction (PPI) networks for differentially expressed genes (DEGs) in the brain cortex and choroid plexus. Topologically crucial genes were identified, and MCODE clusters were analyzed for functional enrichment using the STRING database. Genes related to neurological symptoms (headache, seizure, stroke, meningitis, encephalitis) were extracted from the Comparative Toxicogenomics Database (CTD), and their associations with MCODE clusters were assessed via Fisher's exact test. Crucial gene interactions with FDA-approved drugs were also investigated.

Results

We identified a cluster of heat shock protein (HSP) genes (HSP90AA1, HSPA1A, HSPA1B, HSPB1, HSPH1, HSPA5, DNAJB1, FKBP5) significantly correlated with all neurological manifestations. KEGG pathway enrichment showed associations with immune processes, neurodegenerative diseases (Parkinson's, Alzheimer's, Huntington's), virus-related pathways (Influenza A, Epstein-Barr, Measles), and pathways activated in viral infections. FKBP5, a key Hsp90 co-chaperone, interacts most with drugs that affect the nervous system in our drug-gene network.

Conclusions

Shedding light on the molecular mechanisms behind COVID-19 neurological manifestations and possible drugs could pave the way for better managing future neurotrophic viruses.

在COVID-19大流行期间，报告的神经系统症状和潜在综合征，如缺血性卒中、癫痫发作和脑炎，突出了SARS-CoV-2对神经系统的影响。我们采用系统生物学方法分析组学转录数据，探索COVID-19神经系统并发症的分子机制。方法从基因表达综合（GEO）数据集中检索COVID-19患者死后脑数据，构建脑皮层和脉络膜丛差异表达基因（DEGs）的蛋白-蛋白相互作用（PPI）网络。在拓扑结构上鉴定了关键基因，并利用STRING数据库分析了MCODE簇的功能富集。从比较毒物基因组学数据库（CTD）中提取与神经系统症状（头痛、癫痫、中风、脑膜炎、脑炎）相关的基因，并通过Fisher精确检验评估它们与MCODE簇的相关性。关键基因与fda批准的药物的相互作用也进行了调查。结果热休克蛋白（HSP）基因簇（HSP90AA1、HSPA1A、HSPA1B、HSPB1、HSPH1、HSPA5、DNAJB1、FKBP5）与所有神经系统表现均有显著相关性。KEGG通路富集显示与免疫过程、神经退行性疾病（帕金森病、阿尔茨海默病、亨廷顿病）、病毒相关通路（甲型流感、爱普斯坦-巴尔病、麻疹）和病毒感染激活的通路相关。FKBP5是一个关键的Hsp90共同伴侣，在我们的药物基因网络中与影响神经系统的药物相互作用最多。结论揭示COVID-19神经学表现背后的分子机制和可能的药物为更好地管理未来的神经营养病毒铺平了道路。

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引用次数: 0

The synergistic effect of HIF-1α, VEGFA and VEGFR2 gene polymorphisms in the pathogenesis of acute myeloid leukemia HIF-1α、VEGFA和VEGFR2基因多态性在急性髓性白血病发病机制中的协同作用

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-05-30 DOI: 10.1016/j.humgen.2025.201432

Mayuri Goswami , Shantipriya Kakati , Jina Bhattacharyya , Natasha Kashyap , Snigdha Jyoti Das , Mafidul Islam , Sujoy Bose , Purabi Deka Bose

Objectives

This study aims to analyze polymorphisms and the differential mRNA expression of some hypoxia-angiogenesis pathway genes in acute myeloid leukemia (AML) cases and correlate these findings with disease pathogenesis.

Patients and methods

The study included 64 de novo AML cases with mean age of 29.45 ± 16.49 years and sex ratio of 1.46:1.00; along with 64 age and sex-matched controls. With specific standardized primers and Taq polymerase enzyme, the targeted genes were amplified using PCR. Further RFLP analysis was done using specific restriction endonuclease enzymes to detect polymorphisms. Semi-quantitative real-time PCR was performed for gene expression studies at mRNA level.

Results

Higher prevalence of CT and TT genotypes of HIF-1α rs11549465 SNP, CA and AA genotypes of VEGFA rs699947 SNP and AT and TT genotypes of VEGFR2 rs1870377 SNP were found in cases as compared to control. The co-occurrence of T allele of HIF-1α rs11549465, A allele of VEGFA rs699947 and T allele of VEGFR2 rs1870377 SNPs were found to be common in cases indicating higher risk of the disease. mRNA expression analysis revealed upregulation of HIF-1α, VEGFA and VEGFR2 by 9.92 ± 7.28, 9.05 ± 5.87 and 2.11 ± 0.48 fold respectively in patients. Significant correlation (p < 0.01) was found between the expression of HIF-1α and VEGFA genes. Correlation analysis between genotypes and mRNA expression profiles detected the role of T allele of HIF-1α rs11549465 SNP, A allele of VEGFA rs699947 SNP and AT genotype of VEGFR2 rs1870377 SNP in the overexpression of respective genes.

Conclusion

Synergistic association of T allele of HIF-1α rs11549465, A allele of VEGFA rs699947 and AT genotype of VEGFR2 rs1870377 SNPs have been identified that might promote the pathogenesis of AML.

目的分析急性髓性白血病（AML）中缺氧血管生成通路基因的多态性和mRNA表达差异，并探讨其与疾病发病机制的关系。患者与方法纳入64例新发AML患者，平均年龄29.45±16.49岁，性别比为1.46:1.00；还有64名年龄和性别匹配的对照组。利用特异的标准引物和Taq聚合酶，用PCR扩增目标基因。进一步使用特异性限制性内切酶进行RFLP分析以检测多态性。采用实时半定量PCR技术在mRNA水平上进行基因表达研究。结果病例中HIF-1α rs11549465 SNP的CT和TT基因型、VEGFA rs699947 SNP的CA和AA基因型、VEGFR2 rs1870377 SNP的AT和TT基因型的发生率均高于对照组。HIF-1α rs11549465的T等位基因、VEGFA rs699947的A等位基因和VEGFR2 rs1870377 snp的T等位基因共同出现在疾病高风险的病例中是常见的。mRNA表达分析显示患者HIF-1α、VEGFA和VEGFR2分别上调9.92±7.28倍、9.05±5.87倍和2.11±0.48倍。显著相关(p <；HIF-1α与VEGFA基因表达差异达0.01)。基因型与mRNA表达谱的相关性分析检测了HIF-1α rs11549465 SNP的T等位基因、VEGFA rs699947 SNP的A等位基因和VEGFR2 rs1870377 SNP的AT基因型在各自基因过表达中的作用。结论HIF-1α rs11549465等位基因T、VEGFA rs699947等位基因和VEGFR2 rs1870377 snp基因型的协同关联可能促进AML的发病。

{"title":"The synergistic effect of HIF-1α, VEGFA and VEGFR2 gene polymorphisms in the pathogenesis of acute myeloid leukemia","authors":"Mayuri Goswami , Shantipriya Kakati , Jina Bhattacharyya , Natasha Kashyap , Snigdha Jyoti Das , Mafidul Islam , Sujoy Bose , Purabi Deka Bose","doi":"10.1016/j.humgen.2025.201432","DOIUrl":"10.1016/j.humgen.2025.201432","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to analyze polymorphisms and the differential mRNA expression of some hypoxia-angiogenesis pathway genes in acute myeloid leukemia (AML) cases and correlate these findings with disease pathogenesis.</div></div><div><h3>Patients and methods</h3><div>The study included 64 de novo AML cases with mean age of 29.45 ± 16.49 years and sex ratio of 1.46:1.00; along with 64 age and sex-matched controls. With specific standardized primers and Taq polymerase enzyme, the targeted genes were amplified using PCR. Further RFLP analysis was done using specific restriction endonuclease enzymes to detect polymorphisms. Semi-quantitative real-time PCR was performed for gene expression studies at mRNA level.</div></div><div><h3>Results</h3><div>Higher prevalence of CT and TT genotypes of HIF-1α rs11549465 SNP, CA and AA genotypes of VEGFA rs699947 SNP and AT and TT genotypes of VEGFR2 rs1870377 SNP were found in cases as compared to control. The co-occurrence of T allele of HIF-1α rs11549465, A allele of VEGFA rs699947 and T allele of VEGFR2 rs1870377 SNPs were found to be common in cases indicating higher risk of the disease. mRNA expression analysis revealed upregulation of HIF-1α, VEGFA and VEGFR2 by 9.92 ± 7.28, 9.05 ± 5.87 and 2.11 ± 0.48 fold respectively in patients. Significant correlation (<em>p</em> < 0.01) was found between the expression of HIF-1α and VEGFA genes. Correlation analysis between genotypes and mRNA expression profiles detected the role of T allele of HIF-1α rs11549465 SNP, A allele of VEGFA rs699947 SNP and AT genotype of VEGFR2 rs1870377 SNP in the overexpression of respective genes.</div></div><div><h3>Conclusion</h3><div>Synergistic association of T allele of HIF-1α rs11549465, A allele of VEGFA rs699947 and AT genotype of VEGFR2 rs1870377 SNPs have been identified that might promote the pathogenesis of AML.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201432"},"PeriodicalIF":0.5,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling a rare genetic enigma: A father-son duo with alagille syndrome and a novel pathogenic JAG1 variant – Case report and literature review 揭示一个罕见的遗传之谜：一对父子与alagille综合征和一种新的致病JAG1变异-病例报告和文献复习

IF 0.5 Q4 GENETICS & HEREDITY

Human Gene

Pub Date : 2025-05-30 DOI: 10.1016/j.humgen.2025.201428

Hemlata Wadhwani Bhatia , Firoz Ahmad , Sapna Sandal , Raj Shingala , Mukesh Kumar , Amit Yadav , Anindyajit Banerjee , Pooja Chaudhary , Spandan Chaudhary , Neeraj Arora

Alagille syndrome (ALGS) is a rare multisystem disorder primarily caused by alterations in the JAG1 gene and, less frequently, in NOTCH2. The syndrome exhibits variable phenotypic expression, making diagnosis challenging. We report a novel heterozygous frameshift deletion variant, c.1019del (p.Cys340Serfs*72), in exon 8 of JAG1, identified in a father-son duo. This variant, located within the evolutionarily conserved EGF-like repeat domain, is predicted to be pathogenic based on its absence in population databases, in silico predictions, and clinical correlation. The father exhibited chronic cholestasis, ductal paucity, and atypical ocular findings, while the son displayed dysmorphic facies, skeletal anomalies, and hearing loss. This case highlights distinct phenotypic variations within the same family despite sharing the same JAG1 variant. Notably, features such as keratoconus, KF ring, tessellated fundus, hyperemic disc, CTEV, and inner ear anomalies have not been previously documented. It underscores the critical role of deep phenotyping, thorough family history re-evaluation, and early genetic diagnosis in ensuring timely intervention.

Alagille综合征（ALGS）是一种罕见的多系统疾病，主要由JAG1基因的改变引起，NOTCH2基因的改变较少。该综合征表现出可变的表型表达，使诊断具有挑战性。我们报道了一个新的杂合移码缺失变异，c.1019del (p.Cys340Serfs*72)，位于JAG1的外显子8上，在一对父子中被发现。该变异位于进化上保守的egf样重复结构域内，根据其在人群数据库、计算机预测和临床相关性中的缺失，预测其具有致病性。父亲表现为慢性胆汁淤积、导管缺乏和非典型眼部表现，而儿子表现为畸形相、骨骼异常和听力丧失。尽管具有相同的JAG1变异，但该病例突出了同一家族中不同的表型变异。值得注意的是，圆锥角膜、KF环、基底块化、椎间盘充血、CTEV和内耳异常等特征以前没有文献记载。它强调了深层表型，彻底的家族史重新评估和早期遗传诊断在确保及时干预中的关键作用。

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引用次数: 0