Human Gene最新文献

{"title":"Altered expression patterns of lncRNA MEG3 and LINC01611 in patients with colorectal cancer","authors":"Niloofar Faraji ,&nbsp;Mohammad Almasi ,&nbsp;Majid Mirmazloumi ,&nbsp;Nasim Padasht ,&nbsp;Sahand Sadat Mansouri ,&nbsp;Fatemeh Ghaderibarmi ,&nbsp;Haniyeh Royatpour ,&nbsp;Fatemeh Modaresi ,&nbsp;Kourosh Kazempour Samak ,&nbsp;Fahimeh Abedini Bajgiran ,&nbsp;Tahereh Zeinali ,&nbsp;Narges Eslami ,&nbsp;Dariush Shanehbandi ,&nbsp;Ali Salehzadeh","doi":"10.1016/j.humgen.2025.201470","DOIUrl":"10.1016/j.humgen.2025.201470","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a major global health challenge, with long non-coding RNAs (lncRNAs) gaining attention as potential diagnostic biomarkers. This study aimed to experimentally validate bioinformatics findings on the expression patterns of maternally expressed gene 3 (MEG3) and LINC01611 in CRC patients from a specific ethnic population while considering associated risk factors. This in vitro study initially recruited 50 patients from a single ethnic group, with 48 completing the analysis after the exclusion of two samples. Two lncRNAs, MEG3 and LINC01611, were selected using Gene Expression Omnibus (GEO) microarray data and identified via R/BioConductor. Paired tissue samples (tumor and adjacent margins) were collected during surgery, and RNAs were extracted. Demographic and clinical data of patients were recorded, and gene expression was analyzed using quantitative real-time PCR (qPCR), with GAPDH as the internal control. Data analysis was performed using GraphPad Prism and SPSS software, with the significance level set at <em>P</em> &lt; 0.05. The mean age of the patients was 59.5 ± 3.53 years, with 58.3 % (<em>n</em> = 28) being male, and 37.5 % of the patients had a history of smoking. The majority of patients had poorly differentiated (41.7 %) and stage II tumor (43.8 %), with lymph node metastasis commonly observed (60.4 %). The Wilcoxon signed-rank test revealed significant downregulation of MEG3 (32.396 fold change)and LINC01611(38.923 fold change) in tumor tissues compared to adjacent margins. A family history of CRC was associated with higher expression levels of MEG3 (1.48-fold, <em>P</em> = 0.038) and LINC01611 (1.03-fold, <em>P</em> = 0.007) in both tumor and margin tissues. Multivariable regression analysis demonstrated that lncRNAs had a significant association with tumor differentiation (<em>P</em> &lt; 0.05), while other variables showed no statistically significant association (<em>P</em> &gt; 0.05). Also, positive correlations were observed between MEG3 and LINC01611 expression levels in tumor (<em>r</em> = 0.649, <em>P</em> &lt; 0.001) and margin (<em>r</em> = 0.424, <em>P</em> = 0.003) tissues. The significant downregulation of MEG3 and LINC01611 in tumor tissues compared to adjacent margin tissues highlights their potential role as tumor suppressors in CRC. These findings support further investigation into these lncRNAs as diagnostic biomarkers.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201470"},"PeriodicalIF":0.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931728","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":"Regulatory Axis of circMYO9B and hsa-miR-3529-5p in modulating the breast Cancer biomarker MUC1","authors":"Farnaz Nourmohammadian Dehkordi ,&nbsp;Fatemeh Chaharlang ,&nbsp;Niosha Yahyavi ,&nbsp;Sadaf Gilanian ,&nbsp;Anosha Yahyavi kalkhoran ,&nbsp;Mohamadali Naderi ,&nbsp;Maryam Yousefi ,&nbsp;Nasrin Fattahi Dolatabadi","doi":"10.1016/j.humgen.2025.201468","DOIUrl":"10.1016/j.humgen.2025.201468","url":null,"abstract":"<div><h3>Purpose</h3><div>Breast cancer (BC) is the most prevalent and lethal cancer among women worldwide. Overexpression of the MUC1 gene is observed in approximately 40 % of BC cases. Additionally, mucin-1-derived antigens are recognized as significant serum biomarkers for BC. Identifying genetic regulators of MUC1 may reveal novel pathways for managing and treating BC. This study investigates the regulatory relationship between circMYO9B, hsa-miR-3529-5p, and MUC1 expression.</div></div><div><h3>Methods</h3><div>We utilized circAtlas, CircNet, and miRWalk databases to predict interactions between circMYO9B and hsa-miR-3529-5p and between hsa-miR-3529-5p and MUC1. RNA22 and RNAhybrid-BiBiServe2 confirmed an 82 % high-binding affinity between hsa-miR-3529-5p and MUC1. Experimental validation included RT-qPCR to quantify circMYO9B, hsa-miR-3529-5p, and MUC1 expression levels. Functional assays were performed by constructing plasmids for circMYO9B, hsa-miR-3529-5p, and MUC1, transfecting them into HEK293T cells, and conducting dual luciferase reporter assays.</div></div><div><h3>Result</h3><div>Our results demonstrate that circMYO9B interacts directly with hsa-miR-3529-5p, functioning as a sponge to regulate MUC1 expression in BC. This regulatory axis involving circMYO9B and hsa-miR-3529-5p provides insights into the molecular mechanisms underlying MUC1 dysregulation. MUC1, a key BC gene and marker, may be influenced by this interaction, emphasizing its potential as a target for therapeutic and diagnostic strategies. Subsequent cell viability assays confirmed that overexpression of miR-3529-5p significantly reduced MCF7 cell survival, suggesting an increase in apoptosis.</div></div><div><h3>Discussion</h3><div>This study provides valuable insights into the molecular mechanisms underlying MUC1 regulation and emphasizes the importance of miR-3529 and circMYO9B in modulating MUC1 expression, which may have implications for targeted therapies and diagnostic strategies in breast cancer.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201468"},"PeriodicalIF":0.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044156","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":"A systems biology approach to uncover CNV-driven lncRNA regulatory networks in HPV-associated head and neck squamous cell carcinoma","authors":"Avantika Agrawal,&nbsp;Pubali Bhattacharjee,&nbsp;Swapnil Kumar,&nbsp;Vaibhav Vindal","doi":"10.1016/j.humgen.2025.201469","DOIUrl":"10.1016/j.humgen.2025.201469","url":null,"abstract":"<div><div>Copy number variations (CNVs) have been identified as critical contributors to head and neck squamous cell carcinoma (HNSCC) pathogenesis. Multi-omics analyses offer a comprehensive understanding of its underlying genetic complexities. Therefore, this study aims to examine the CNV-driven long non-coding RNAs (lncRNAs) influencing global regulatory triplet networks (lncRNA–miRNA–mRNA) in HPV-positive and HPV-negative HNSCC subtypes. Differential expression of miRNAs, mRNAs, and CNV-associated lncRNAs were identified using TCGA-HNSCC data. Subsequently, target prediction analyses enabled the construction of CNV-driven global triplet networks specific to HPV status. Gene Ontology (GO) analysis revealed that mRNAs in HPV-positive HNSCC were enriched in cancer-associated processes such as cell proliferation and extracellular matrix (ECM) organization. In contrast, those in HPV-negative HNSCC were primarily enriched in tissue remodeling, development, and cancer progression. KEGG pathway enrichment further supported these findings. The relationship between the CNV of lncRNA MCCC1-AS1 and its expression has revealed that there was no correlation between them in the HPV-positive HNSCC, while in the HPV-negative HNSCC, the gene expression of lncRNA MCCC1-AS1 was correlated with the CNV status. Survival analysis disclosed that the patient with a copy number gain of MCCC1-AS1 was associated with a shorter survival time, suggesting its potential as a prognostic biomarker. These findings highlight the significance of CNV-driven lncRNAs in the molecular landscape of HNSCC and suggest that MCCC1-AS1 may serve as a promising target for further investigation in diagnostic and therapeutic strategies.</div></div>","PeriodicalId":29686,"journal":{"name":"Human Gene","volume":"46 ","pages":"Article 201469"},"PeriodicalIF":0.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144912332","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":"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}