Human Gene最新文献

{"title":"Mapping the transcriptional architecture of glioblastoma at the single-cell level: Decoding heterogeneity, angiogenesis, and mesenchymal shifts","authors":"Naureen Mallick,&nbsp;Reaz Uddin","doi":"10.1016/j.humgen.2025.201467","DOIUrl":"10.1016/j.humgen.2025.201467","url":null,"abstract":"<div><div>Glioblastoma (GBM), a grade IV glioma, is the most aggressive and fatal primary brain tumor, accounting for 48 % of all Central Nervous System tumors. Despite advancements in therapeutic strategies, GBM remains highly resistant to treatment, with a median survival time of just 14 months. This study aimed to identify molecular signature genes associated with GBM heterogeneity using scRNA-seq datasets from 10× Genomics. Two scRNA-seq datasets were processed through the Cell Ranger pipeline, followed by quality control, normalization, and scaling. After data integration using R, Principal Component Analysis was performed, and clusters were visualized using UMAP. A total of 2772 DEGs were identified, of which 95 DEGs met the threshold of logFC≥4 and p-adj ≤ 0.05. These DEGs were significantly enriched in angiogenesis and the PI3K signaling pathway, associated with poor prognosis. Principal Component Analysis revealed 15 principal components, with the first four accounting for the greatest variance. UMAP clustering identified 13 distinct cell clusters, which were annotated using the HPCA reference dataset, revealing enrichment in astrocytes, immune cells, and other tumor-associated cell types. A PPI network was constructed using the STRING database and visualized in Cytoscape, leading to the identification of three mesenchymal hub genes—KDA, PDGFRB, and CXCL12—as key angiogenic markers in GBM. The identified DEGs and hub genes were further validated using GEPIA2 and GSEA. This study provides novel insights into GBM heterogeneity and angiogenic biomarkers, potentially guiding future therapeutic strategies. Nevertheless, additional experimental validation is required to fully understand their role in GBM pathogenesis.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201467"},"PeriodicalIF":0.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887251","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}

{"title":"Transcriptomic meta-analysis of sarcoidosis peripheral blood using STARGEO identifies immune signatures and potential biomarkers","authors":"Maya Hammonds ,&nbsp;Sarah Voskamp ,&nbsp;Martha Londoni ,&nbsp;Peter Wearden ,&nbsp;Jennifer Nelson","doi":"10.1016/j.humgen.2025.201460","DOIUrl":"10.1016/j.humgen.2025.201460","url":null,"abstract":"<div><div>Over 90 % of sarcoidosis patients have pulmonary and mediastinal involvement, and late-stage disease may necessitate heart or lung transplantation. This study investigated the molecular mechanisms underlying sarcoidosis, a complex inflammatory disease, by analyzing differential gene expression patterns in peripheral blood samples. The Search Tag Analyze Resource for NCBI's Gene Expression Omnibus (STARGEO) platform was utilized to identify 218 sarcoidosis and 271 non-sarcoidosis peripheral blood samples. iPathwayGuide identified 639 genes with significant differential expression between sarcoidosis and control samples. The most upregulated genes were FCGR1CP, FCGR1B, PANDAR, DEFA1B, ANKRD22, and CARD17. Upstream regulators showing significant activation included IRF9, STAT2, IFNβ1, IFNG, and IRF7, which are largely involved in inflammatory responses. The top differentially expressed pathways were NOD-like receptor signaling, HSV-1 infection, Influenza A, COVID-19, and the intestinal immune network for IgA production. Differentially expressed genes and pathways play a large role in the immune system's response and regulation. These findings support the known involvement of specific immune responses in the pathogenesis of sarcoidosis. Notably, pathways upregulated in the immune response against several common viruses are also activated in sarcoidosis. The identified differentially expressed genes may serve as potential therapeutic targets, warranting further investigation.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201460"},"PeriodicalIF":0.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144887347","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}

{"title":"Adiponectin gene polymorphism and TyPE 2 diabetes MellitUS: Contrasting genetic RISKS in overdominant vs recessive and allele models – an updated meta – analysis","authors":"Santhini Gopalakrishnan ,&nbsp;Santhi Priya Sobha ,&nbsp;Karpagavel Lakshmanan","doi":"10.1016/j.humgen.2025.201463","DOIUrl":"10.1016/j.humgen.2025.201463","url":null,"abstract":"<div><h3>Background</h3><div>Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder and adipokines such as adiponectin plays a crucial role in the development of T2DM. Adiponectin is encoded by APM1/ADIPOQ gene and polymorphism has been associated with T2DM. The present study aims to determine the overall effect of major SNP of adiponectin gene with T2DM risk.</div></div><div><h3>Methods</h3><div>A through literature search was conducted to identify suitable studies and data was extracted. The association of SNP with T2DM was determined using odds ratio (OR) with 95 % C.I.</div></div><div><h3>Result</h3><div>Allele contrast and recessive model of rs16861194(−11426 A &gt; G), rs266729(−1137C &gt; G), rs2241766(+45 T &gt; G), rs17300539(−11,391 G &gt; A) and rs822396(−3971 G &gt; A) genotype of the APM1/ADIPOQ gene was associated with reduced T2DM risk. The African and Asian population subgroup demonstrated lower T2DM risk under allele contrast and recessive model of rs16861194 and rs2241766 while Caucasian was associated with reduced risk in recessive model of rs266729. The rs822396 variant demonstrated lower risk under allele contrast and recessive model in Asian subgroup. The rs2241767(+346 A &gt; G) polymorphism was associated with reduced T2DM risk under allele contrast and in subgroup analysis only African population showed significant association. In contrast, the over dominant model was associated with increased T2DM risk in rs16861194, rs266729, rs182052, rs2241766, rs17300539 and rs822396. The African and Asian ethnicity demonstrated an increased risk in over dominant model with rs16861194 and rs2241766 while Asian ethnicity showed significant association under over dominant model in rs182052 and rs822396. The rs3774261(+712 A &gt; G) and rs1501299(+276G &gt; T) showed no association with T2DM risk.</div></div><div><h3>Conclusion</h3><div>The major polymorphism of adiponectin showed increased risk under overdominant model while showed a reduced risk under allele and recessive genetic model.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201463"},"PeriodicalIF":0.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879614","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}

{"title":"The interplay between IL-18 rs1946518 polymorphism, TSH dysregulation, and vitamin D3 deficiency in Hashimoto's thyroiditis","authors":"Noor Al-Huda Saber Sadiq,&nbsp;Dhifaf Zeki Aziz","doi":"10.1016/j.humgen.2025.201465","DOIUrl":"10.1016/j.humgen.2025.201465","url":null,"abstract":"<div><h3>Background</h3><div>Hashimoto's thyroiditis (HT) is an autoimmune thyroid disorder shaped by both genetic predisposition and environmental influences. One gene of growing interest is interleukin-18 (IL-18), particularly its rs1946518 (T/G) promoter polymorphism, which may affect inflammatory responses. Meanwhile, vitamin D3 has emerged as a key immunomodulatory factor, yet its interaction with genetic markers in HT remains unclear.</div></div><div><h3>Objective</h3><div>The primary objective of this study was to examine the potential role of the IL-18 gene promoter polymorphism (rs1946518, T/G) in the development of Hashimoto's thyroiditis (HT) among Iraqi patients. The investigation focused on whether this genetic variation affects serum IL-18 levels and contributes to immune and endocrine disturbances commonly observed in HT, including altered levels of thyroid-stimulating hormone (TSH), vitamin D3, and thyroid-specific autoantibodies (anti-TPO and anti-Tg). To further explore the functional implications of IL-18 in the disease process, molecular docking analysis was conducted to evaluate the potential interaction between IL-18 and active vitamin D3 [1,25(OH)₂D₃], aiming to examine the potential molecular interaction how vitamin D may modulate inflammatory responses in HT.</div></div><div><h3>Methods</h3><div>A total of 100 participants were included in a case-control design: 60 patients with HT and 40 matched health controls. Genotyping for rs1946518 was performed using Tetra-ARMS PCR. Serum levels of IL-18, 25(OH)D₃, TSH, anti-TPO, and anti-Tg were measured. Statistical comparisons and molecular docking analyses were conducted to understand both genetic and biochemical patterns.</div></div><div><h3>Results</h3><div>Carriers of the G allele showed significantly higher IL-18 levels, elevated TSH and autoantibodies, and lower vitamin D3 compared to TT/TG genotypes. Newly diagnosed patients had the highest IL-18 and lowest vitamin D3 concentrations. Molecular docking indicated a stable interaction between IL-18 and 1,25(OH)₂D₃, suggesting vitamin D might directly influence IL-18 function.</div></div><div><h3>Conclusion</h3><div>The <em>IL-18</em> rs1946518 G allele may predispose individuals to stronger inflammatory activity in HT, while concurrent vitamin D3 deficiency could amplify this response.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201465"},"PeriodicalIF":0.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144867063","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}

{"title":"Selected SNPs in the BDNF and DRD2 genes and their associations with antipsychotic-induced weight gain in a Sri Lankan cohort","authors":"Kajan Muneeswaran ,&nbsp;Varuni A. de Silva ,&nbsp;Madhubhashinee Dayabandara ,&nbsp;Raveen Hanwella ,&nbsp;Naduviladath Vishvanath Chandrasekharan","doi":"10.1016/j.humgen.2025.201464","DOIUrl":"10.1016/j.humgen.2025.201464","url":null,"abstract":"<div><div>Antipsychotic-induced weight gain (AIWG) is a prevalent and clinically significant side effect that compromises treatment adherence and exacerbates metabolic health risks in individuals receiving antipsychotic medication. While several genetic variants have been implicated in modulating AIWG risk, their population-specific pharmacogenetic architecture remains underexplored in South Asian settings. This study investigated the associations of four SNPs from two genes, rs6265 (<em>BDNF</em> gene), rs1799732, rs1800497, and rs4436578 (<em>DRD2</em> gene), with AIWG in a Sri Lankan schizophrenia cohort (<em>n</em> = 304). SNPs were genotyped via competitive amplification of differentially melting amplicons (CADMA) with high-resolution melt analysis (HRMA) and validated via the MassARRAY System. Statistical analyses, including association, and interaction analyses, were performed using the SNPstats online tool. Genotyping and association analyses revealed marginal association of rs6265 (T allele) with weight gain (OR = 3.25, 95 % CI: 0.85–12.51, <em>p</em> = 0.068), while a protective role for the A allele of rs1800497 was also identified (OR = 0.58, 95 % CI: 0.36–0.91, <em>p</em> = 0.018). This study highlights the utility of integrating genetic screening into psychiatric care to guide personalized treatment strategies and mitigate adverse drug effects in underrepresented populations.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201464"},"PeriodicalIF":0.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144860303","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}

{"title":"Association of Gγ-158C > T XmnI polymorphism with elevated HbF percentage in Sickle Cell Anemia patients: Evidence from a case-control study and meta-analysis","authors":"Satyabrata Meher ,&nbsp;Atanu Kumar Thakur ,&nbsp;Sushil Kumar Sahu ,&nbsp;Siris Patel ,&nbsp;Bimal Krushna Panda ,&nbsp;Kishalaya Das ,&nbsp;Snehadhini Dehury ,&nbsp;Sarmila Sahoo ,&nbsp;Mamata Pandey ,&nbsp;Bisnu Prasad Dash","doi":"10.1016/j.humgen.2025.201462","DOIUrl":"10.1016/j.humgen.2025.201462","url":null,"abstract":"<div><h3>Background</h3><div>Sickle Cell Anemia (SCA) is a monogenic disorder characterized by significant clinical heterogeneity, much of which is modulated by fetal hemoglobin (HbF) levels. The -158C &gt; T <em>Xmn</em>I polymorphism (rs7482144) in the Gγ-globin gene promoter is a known genetic determinant of HbF expression. This study investigates the association of the Gγ-158C &gt; T XmnI polymorphism with HbF levels in SCA patients from Eastern India and global evidence through a meta-analysis.</div></div><div><h3>Methods</h3><div>A case-control study was conducted involving 100 SCA patients and 50 healthy controls from Eastern India. Genotyping for the Gγ-158C &gt; T XmnI polymorphism was performed using PCR-RFLP. Clinical and hematological parameters, including HbF percentage, were assessed. Genotype and allele frequencies were compared between cases and controls. A meta-analysis was performed, incorporating 591 SCA cases and 531 controls were included from 10 published studies satisfying the criteria, including the present investigation, evaluating various genetic models (T vs C, TT vs CC, TT vs CC + CT, CT vs CC, TT + CT vs CC). Heterogeneity and publication bias were assessed using standard statistical methods.</div></div><div><h3>Results</h3><div>SCA patients exhibited significantly higher frequencies of the T allele (76.5 %) and TT genotype (66 %) compared to controls (T allele: 37 %, TT genotype: 22 %). HbF levels were significantly elevated in TT homozygotes (21.8 ± 8.57 %) compared to CT (17.5 ± 9.51 %) and CC (13.01 ± 5.35 %) genotypes (<em>p</em> &lt; 0.003). The T allele and TT genotype were strongly associated with SCA, with odds ratios (OR) of 0.18 (95 % CI: 0.11–0.30, <em>p</em> &lt; 0.0001) and 0.09 (95 % CI: 0.04–0.23, p &lt; 0.0001), respectively. Meta-analysis confirmed a significant association between the T allele and increased HbF levels in SCA across populations (T vs C: pooled OR = 0.359, 95 % CI: 0.200–0.643, <em>p</em> = 0.001; TT vs CC: pooled OR = 0.186, 95 % CI: 0.107–0.321, <em>p</em> = 0.000). Moderate heterogeneity was observed for some comparisons (I² up to 77.6 %), but no significant publication bias was detected.</div></div><div><h3>Conclusion</h3><div>The Gγ-158C &gt; T <em>Xmn</em>I polymorphism is significantly associated with increased HbF levels and a protective effect in SCA patients, both in the Eastern Indian population and globally. These findings highlight the importance of this genetic marker for prognostication and potential therapeutic targeting in SCA.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201462"},"PeriodicalIF":0.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144831344","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}

{"title":"Structural and functional analysis of SOX9 mutations in disorders of sex development (DSD): Integration of clinical data and in silico modeling","authors":"Fatou Diop Gueye ,&nbsp;Mama Sy Diallo ,&nbsp;Arame Ndiaye ,&nbsp;Mame Venus Gueye ,&nbsp;Ndiaga Diop ,&nbsp;Adji Dieynaba Diallo ,&nbsp;Rokhaya Ndiaye ,&nbsp;Oumar Faye","doi":"10.1016/j.humgen.2025.201461","DOIUrl":"10.1016/j.humgen.2025.201461","url":null,"abstract":"<div><div>The <em>SOX9</em> gene, located on chromosome 17q24, belongs to the <em>SOX</em> family of transcription factors and shares over 70 % homology with <em>SRY</em>. It plays a central role in testis differentiation and cartilage formation, notably by regulating key genes such as <em>AMH</em>. Mutations in <em>SOX9</em> are known to cause Disorders of Sex Development (DSD) and skeletal malformations such as campomelic dysplasia.</div></div><div><h3>Objective</h3><div>This study aimed to analyze the structural and functional impact of <em>SOX9</em> mutations identified in DSD patients, using in silico predictive tools including IntFOLD, to evaluate changes in protein conformation and correlate them with observed phenotypes.</div></div><div><h3>Methods</h3><div>Twenty-eight patients with DSD (46,XX or 46,XY karyotypes) were enrolled. The <em>SRY</em> and <em>SOX9</em> genes were amplified by PCR and sequenced. Four 46,XX patients were found to be <em>SRY</em>-positive, and two 46,XY patients were <em>SRY</em>-negative. Ten <em>SOX9</em> variants were identified in 12 patients, including two novel intronic variants, two in the 3′UTR region, three synonymous, and three non-synonymous coding variants. All variants were found in the heterozygous state, and the presence of a normal allele was used to assess its functional implications.</div></div><div><h3>Results</h3><div>Non-synonymous mutations located within the <em>HMG</em> and <em>dimerization domains</em> were predicted to be deleterious. 3D modeling using IntFOLD revealed conformational changes, altered protein stability, and disrupted ligand-binding residues. These structural alterations correlated with the DSD phenotypes observed. The overall <em>SOX9</em> structure showed a largely disordered organization, with ordered segments within key functional domains.</div></div><div><h3>Conclusion</h3><div>Our findings confirm the role of <em>SOX9</em> in the etiology of DSD and highlight the relevance of structural modeling for interpreting rare variants. The integration of clinical, genetic, and in silico data contributes to a better understanding of sex differentiation mechanisms and may support improved molecular diagnosis of DSD.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201461"},"PeriodicalIF":0.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144831345","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}

{"title":"Computational investigation of lignans as potential target for non-alcoholic fatty liver disease: Insights from network pharmacology, docking, DFT, and dynamics simulation analysis","authors":"Rajappan Chandra Satish Kumar ,&nbsp;Akash Jayaraman ,&nbsp;Ramesh Venkatachalapathy","doi":"10.1016/j.humgen.2025.201457","DOIUrl":"10.1016/j.humgen.2025.201457","url":null,"abstract":"<div><div>NAFLD is a major cause of morbidity and mortality worldwide. The present study aims to investigate the therapeutic potential of selected lignans, including 6-hydroxy enterodiol and secoisolariciresinol, against the key molecular targets involved in the pathogenesis of the disease. A network pharmacology approach was employed to elucidate the interaction between the proteins of bioactive compounds and disease targets, while docking and density functional theory (DFT) calculations were conducted to assess the electronic properties and reactivity profiles of the ligands. GO and KEGG pathway enrichment analysis was done to understand the core targets that are involved in various biological pathways and biological functions. Furthermore, dynamic validation of the stability and conformational behavior of the protein-ligand complexes under the physiological condition was done through MM-GBSA free energy calculations, Free Energy Landscape (FEL) mapping, and Principal Component Analysis (PCA). AKT1, CASP3, and IL6 exhibited highly favorable binding free energies, which range from 75.0196 to 75.2026 kcal/mol, indicating the stability and binding of the proteins. Moreover, CASP3 exhibited a low energy gap and a high electrophilicity index, underscoring its potential as an effective electron acceptor. In conclusion, the present computational study provides substantial evidence for the efficacy of a group of peptides as natural therapies for the treatment of nonalcoholic fatty liver disease.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201457"},"PeriodicalIF":0.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749703","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}

{"title":"Post-transcriptional targeting of PCSK9 by microRNAs: From mechanisms to therapeutic potential","authors":"Maryam Mahjoubin-Tehran ,&nbsp;Samaneh Rezaei ,&nbsp;Tannaz Jamialahmadi ,&nbsp;Prashant Kesharwani ,&nbsp;Amirhossein Sahebkar","doi":"10.1016/j.humgen.2025.201456","DOIUrl":"10.1016/j.humgen.2025.201456","url":null,"abstract":"<div><div>The reduction of serum low-density lipoprotein cholesterol (LDL-C) remains a cornerstone in the prevention and management of atherosclerotic cardiovascular disease (ASCVD). Over the past decades, substantial progress has been made in elucidating the molecular mechanisms regulating cholesterol homeostasis, leading to the development of effective LDL-lowering therapies. A pivotal advancement in this field was the identification of proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that plays a critical role in lipid metabolism. PCSK9 promotes the degradation of hepatic LDL receptors (LDL-R), thereby impairing the clearance of circulating LDL-C. The discovery that loss-of-function mutations in PCSK9 confer protection against cardiovascular events has spurred the development of PCSK9-targeted therapies, particularly monoclonal antibodies, which have demonstrated robust efficacy in reducing LDL-C levels and cardiovascular risk. Despite these clinical successes, the intricate regulatory networks governing PCSK9 expression, especially at the post-transcriptional level, remain incompletely understood. Emerging evidence implicates microRNAs (miRNAs) as key modulators of lipid metabolism, including the regulation of PCSK9. These small, non-coding RNAs orchestrate complex gene regulatory circuits and have the potential to fine-tune PCSK9 expression, offering novel therapeutic avenues beyond current pharmacological inhibitors. This review critically examines the current understanding of miRNA-mediated regulation of PCSK9, highlights key miRNAs implicated in this process, and discusses their potential as therapeutic targets or biomarkers in the context of dyslipidemia and cardiovascular disease. Unraveling the interplay between miRNAs and PCSK9 may pave the way for next-generation lipid-lowering strategies with enhanced specificity and efficacy.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201456"},"PeriodicalIF":0.5,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144713760","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}

{"title":"Enhancing network analysis with supervised machine learning and mendelian randomization with unsupervised machine learning to identify core phase separation biomarkers in autoimmune insulin receptoropathy","authors":"Chuyu Liang ,&nbsp;Zhaoxia Yu ,&nbsp;Qiuyi Liang ,&nbsp;Ziran Zeng ,&nbsp;Rongguan Ma ,&nbsp;Wenyan Xie ,&nbsp;Xiao Zhu","doi":"10.1016/j.humgen.2025.201455","DOIUrl":"10.1016/j.humgen.2025.201455","url":null,"abstract":"<div><h3>Background</h3><div>Recent research has focused on the link between phase separation genes and immunity, alongside their potential role in insulin signaling modulation. Autoimmune insulin receptoropathy (AIR), characterized by sporadic hypoglycemia, lacks reliable molecular markers for early detection.</div></div><div><h3>Methods</h3><div>Phase separation genes associated with AIR were analyzed using differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Disease Ontology (DO) explored biological differences. A protein-protein interaction (PPI) network and machine learning (SVM-REF, RandomForest) identified core phase separation genes. Functional insights were gained through correlation, differential expression, and single-gene GSEA analyses. Marker gene activity was assessed via single-sample GSEA. Mendelian randomization (MR) examined potential causal links between DO results and the disease, validating associations with phase separation genes. Unsupervised machine learning reinforced the findings.</div></div><div><h3>Results</h3><div>Differential gene expression and WGCNA identified 2944 differentially expressed genes and 18 co-expression modules in AIR. The darkturquoise module, showing a potential inverse relationship with disease status, was selected for further analysis. GSEA revealed up-regulated pathways such as Inositol phosphate metabolism and down-regulated pathways like Drug metabolism. PPI network and machine learning analyses identified 10 core genes closely linked to AIR, demonstrating significant predictive capability and potential as early diagnostic biomarkers.</div></div><div><h3>Conclusions</h3><div>The phase separation genes linked to AIR show strong disease associations, offering potential for early prediction and improved clinical management.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"45 ","pages":"Article 201455"},"PeriodicalIF":0.5,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144704498","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}