Front Genet [JOURNAL]
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200 papers
Preliminary examination of noncoding mutations of esophageal squamous cell carcinoma in African Americans.
Erkizan HV, Wadleigh R
Front Genet · 2026 · PMID 42046719 · Full text
The incidence of esophageal squamous cell carcinoma is geographically heterogeneous and exhibits complex genomic features. We aimed to preliminarily analyze noncoding mutations identified through whole-exome sequencing....
The incidence of esophageal squamous cell carcinoma is geographically heterogeneous and exhibits complex genomic features. We aimed to preliminarily analyze noncoding mutations identified through whole-exome sequencing. Agilent SureSelect XT Human All Exon V6+UTR was used to capture the exome library from 10 African American ESCC patients. After calling variants, we analyzed noncoding mutations using Variant Effect Predictor, CScape-somatic, HumanBase modules and Opencravat. Pathway enrichment analysis was performed using the SIGNOR database via the NDEx IQuery web tool. Our results identified noncoding variants in the 3'UTR, 5'UTR, splice site, and promoter regions. We also observed a nominal enrichment of germline variations in DNA damage repair genes among patients with ESCC.
Circular RNAs in obesity and related metabolic disorders: mechanistic insights and therapeutic perspectives.
Bernal-Vázquez D, Bolaños-Fernández I, Salcedo-Rivas GO … +3 more , Figueroa-Ramírez M, Duttaroy AK, Paul S
Front Genet · 2026 · PMID 42039704 · Full text
Obesity is a multifactorial and chronic metabolic disease strongly linked to type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular complications, and several cancers. Despite advances in pharmacolog...
Obesity is a multifactorial and chronic metabolic disease strongly linked to type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular complications, and several cancers. Despite advances in pharmacological and surgical interventions, long-term management remains suboptimal, emphasizing the need for new molecular targets. Circular RNAs (circRNAs), a unique class of covalently closed non-coding RNAs, have recently emerged as critical regulators of metabolic homeostasis. By acting as microRNA sponges, transcriptional modulators, and protein scaffolds, circRNAs participate in key processes such as adipogenesis, lipid metabolism, inflammation, and insulin signaling. Dysregulated circRNA expression has been implicated in obesity-induced β-cell dysfunction, hepatic steatosis, vascular remodeling, and tumor progression. Their high stability, evolutionary conservation, and tissue-specific expression further highlight their promise as minimally invasive biomarkers and therapeutic candidates for obesity-associated disorders. However, translation to clinical application remains limited due to methodological inconsistencies, lack of standardized quantification, and insufficient functional validation. Future integration of circRNA profiling with multi-omics and genome-editing approaches could accelerate the identification of mechanistic pathways and therapeutic targets, paving the way for precision medicine strategies in obesity and related metabolic diseases.
Epigenetic legacy of early-life undernutrition: methodological lessons from Dutch and Chinese famine studies.
Khatib H, Ellsworth E, Badhwar N
Front Genet · 2026 · PMID 42039703 · Full text
The recent rise in global food insecurity has renewed scientific interest in understanding the long-term health consequences of early-life nutritional deprivation. This study critically evaluates the experimental designs...
The recent rise in global food insecurity has renewed scientific interest in understanding the long-term health consequences of early-life nutritional deprivation. This study critically evaluates the experimental designs and methodological approaches of key publications examining the epigenetic and phenotypic effects of the Dutch and Chinese famines. Specifically, these studies were assessed for sample size, control group selection, relevance of tissue sampling, timing of famine exposure, and the quality of statistical reporting. Research on both famines has centered on prenatal exposure and subsequent health outcomes, providing important insights into how nutritional deprivation may lead to long-lasting epigenetic modifications. These changes have been linked to elevated risks for metabolic, cardiovascular, and neuropsychiatric disorders. Despite these contributions, many studies exhibited notable limitations, including small sample sizes, questionable accuracy in reporting health outcomes, and issues with the selection of control groups. Such methodological shortcomings may have led to the misinterpretation of some findings. Ongoing and recent famines in regions such as Sudan, Somalia, and Gaza-driven by conflict and environmental disasters, including droughts and floods-represent some of the most pressing humanitarian crises of our time. Lessons from studies of the 20th-century Dutch and Chinese famines can inform the design of future research on the biological and intergenerational consequences of famine and trauma. Improved study designs will enhance the ability to generate reliable evidence and guide global health strategies for populations at risk of transgenerational effects from nutritional deprivation.
Editorial: Chromatin modifications and gene expression: from mechanisms to therapeutic implications in disease.
Burlibasa L, Nassa G, Botezatu A … +1 more , Salvati A
Front Genet · 2026 · PMID 42039702 · Full text
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Editorial: APOBEC and ADAR in oncogenesis: from molecular mechanisms to therapeutic targets.
Li X, Wang Y, Mu P
Front Genet · 2026 · PMID 42039701 · Full text
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Correction: Whole-exome sequencing analysis of human semen quality in Russian multiethnic population.
Kolmykov S, Vasiliev G, Osadchuk L … +2 more , Kleschev M, Osadchuk A
Front Genet · 2026 · PMID 42039700 · Full text
[This corrects the article DOI: 10.3389/fgene.2021.662846.].
[This corrects the article DOI: 10.3389/fgene.2021.662846.].
Unraveling quantitative trait loci (QTL) overlapping epigenomic regulatory regions associated with feeding behavior in pigs.
Gervásio IC, Brito LF, Araujo AC … +9 more , Fanalli SL, Silva-Vignato B, Rocha AO, Benfica LF, Fernanda de Oliveira L, Felício Ament AM, Monteiro Moreira GC, Moncau-Gadbem CT, Mello Cesar AS
Front Genet · 2026 · PMID 42039699 · Full text
INTRODUCTION: Feed behavior traits are directly linked to the sustainability of pig production. This study aimed to investigate the genetic basis of feeding behavior traits in Landrace and Yorkshire pigs, focusing on gen...
INTRODUCTION: Feed behavior traits are directly linked to the sustainability of pig production. This study aimed to investigate the genetic basis of feeding behavior traits in Landrace and Yorkshire pigs, focusing on genomic regions, quantitative trait loci (QTL), candidate genes, and metabolic pathways associated with these traits. METHODS: Genome-wide association studies (GWAS) were performed, followed by functional enrichment analyses and integrative bioinformatics approaches to identify biologically relevant genomic regions, candidate genes, and pathways associated with feeding behavior traits. RESULTS: Several candidate genes and transcription factors were identified, including STAT3, STAT5A, STAT5B, RARA, SMAD4, MYC, FOXP3, SP1, NOTCH1, and RXRA. In addition, strong candidate genes such as SLC22A2, CPAMD8, and NKX2-6 were highlighted as potentially influencing feeding behavior traits. DISCUSSION: These findings improve the understanding of the genomic architecture underlying feeding behavior traits and provide valuable insights for the development of more efficient breeding programs, contributing to improved animal production efficiency and welfare.
Genetic distribution of selected obesity-related SNVs in the , , , , , and genes in a Mexico city population.
Perezcano C, Sánchez A, Cendejas G … +3 more , Borrayo F, Pérez-Coria M, Pérez-Hernández G
Front Genet · 2026 · PMID 42039698 · Full text
INTRODUCTION: Obesity represents a significant health challenge worldwide, with an increasing trend and high prevalence in Mexico. This metabolic disease, characterized by an increase in body mass index (BMI), leads to a...
INTRODUCTION: Obesity represents a significant health challenge worldwide, with an increasing trend and high prevalence in Mexico. This metabolic disease, characterized by an increase in body mass index (BMI), leads to abnormal fat accumulation that contributes to several pathologies, and is determined by a complex interaction between diet, lifestyle and genetic factors, such as single nucleotide variants (SNVs) that may influence appetite regulation, adipose tissue function, energy metabolism, reward mechanisms, motivation, food intake behavior control, energy expenditure, fatty acid transport, lipid accumulation, lipolysis, insulin sensitivity, glucose metabolism, among other biochemical processes. However, the frequency of obesity-associated genetic variants remains poorly characterized in Mexican populations-which are highly admixed-as demonstrated by population genetic studies which have established the influence of this admixture in the prevalence and distribution of obesity-related SNVs. METHODS: This descriptive population genetic study aimed to characterize the genotype and allele frequency distributions of six SNVs previously associated with obesity and metabolic traits: rs9939609, rs1800497, rs17782313, rs1799883, rs1042714, and rs4788102 through a cross-sectional design conducted in a cohort from Mexico City ( = 129). RESULTS AND DISCUSSION: The genotyping results revealed substantial variability in allelic frequencies across the analyzed variants, with rs4788102 showing the highest minor allele frequency (MAF) (0.41), followed by rs1800497 (0.32) and rs9939609 (0.31), whereas rs17782313 presented the lowest MAF (0.12). All SNVs were in HWE ( > 0.05). Understanding the prevalence of these obesity-related genetic markers in Mexican populations provides a reference for future genomic and nutrigenomic studies, and may support the development of personalized prevention strategies contributing to deeper insight into the molecular basis of metabolic diseases in Mexico, given the serious public health challenge they represent.
MoJKNet: a jumping knowledge graph framework for multi-omics cancer subtype prediction.
Lou J, Pan X, Wang X
Front Genet · 2026 · PMID 42017142 · Full text
Cancer remains one of the leading causes of morbidity and mortality worldwide and poses a major threat to global public health. Despite substantial advances in early diagnosis and therapeutic strategies, patient outcomes...
Cancer remains one of the leading causes of morbidity and mortality worldwide and poses a major threat to global public health. Despite substantial advances in early diagnosis and therapeutic strategies, patient outcomes vary widely due to the pronounced molecular and clinical heterogeneity of tumors. Accurate identification of cancer subtypes is therefore essential for elucidating tumor heterogeneity, improving prognostic assessment, and enabling precision medicine. In recent years, multi-omics technologies have provided unprecedented opportunities to characterize cancer at multiple molecular layers, including genomic, epigenomic, transcriptomic, and proteomic levels. However, effectively integrating high-dimensional and heterogeneous multi-omics data remains a major challenge. Moreover, many existing graph convolutional network-based integration methods suffer from over-smoothing and limited utilization of deep feature representations, which restrict their ability to capture complex multi-scale relationships inherent in cancer biology. To address these challenges, we propose MoJKNet, a novel multi-omics integration framework for cancer subtype classification. MoJKNet incorporates a jumping knowledge network (JK-Net) to adaptively aggregate node representations across multiple propagation depths, thereby alleviating over-smoothing and enhancing feature extraction within each omics modality. Subsequently, a multimodal autoencoder combined with similarity network fusion (SNF) is employed to capture complementary information across different omics layers. Finally, a graph attention network (GAT) assigns adaptive feature weights to enable accurate cancer subtype prediction. We evaluated MoJKNet on seven cancer types from The Cancer Genome Atlas (TCGA). Experimental results demonstrate that MoJKNet consistently outperforms state-of-the-art methods, including MOGCAN, MOGONET, and MoGCN, in terms of precision, recall, and F1-score, achieving nearly a 10% performance improvement on the COADREAD dataset. Ablation studies further confirm the critical contribution of the jumping knowledge mechanism to improved representation learning. Overall, MoJKNet provides an effective and generalizable solution for multi-omics data integration and cancer subtype classification, with strong potential for downstream biological interpretation and translational applications.
Case Report: Rare triple-line chromosome 9 mosaicism (47,XX,+del(9)(q13)/47,XX,+9/46,XX) associated with severe neurodevelopmental impairment and congenital anomalies.
Zagorac A, Miksić M, Zagradišnik B … +2 more , Korpar B, Kokalj Vokač N
Front Genet · 2026 · PMID 42017141 · Full text
BACKGROUND: Chromosome 9 abnormalities are rare. Full trisomy 9 is mostly incompatible with postnatal survival, whereas mosaic trisomy 9 permits survival with highly variable clinical manifestations. Triple-line mosaicis...
BACKGROUND: Chromosome 9 abnormalities are rare. Full trisomy 9 is mostly incompatible with postnatal survival, whereas mosaic trisomy 9 permits survival with highly variable clinical manifestations. Triple-line mosaicism involving both full trisomy 9 and structural chromosome 9 abnormalities is exceptionally rare. CASE PRESENTATION: A 1-year-old girl, conceived via IVF, had normal nuchal translucency and NIPT. Prenatal ultrasound showed a single umbilical artery, lower abdominal cyst, borderline ventriculomegaly at 28 weeks, and late polyhydramnios. She was born at 40 weeks, 3,430 g, 49 cm, head circumference 36 cm, Apgar 8/9/9, requiring mild oxygen supplementation. At age 1 year, she exhibited dysmorphic facial features (prominent forehead, hypertelorism, upslanting palpebral fissures, short philtrum, low-set mildly dysplastic ears, retrognathia), bilateral ovarian cysts, minimal clinodactyly of the right fifth finger, palmar and plantar crease abnormalities, hemodynamically significant patent ductus arteriosus (PDA), patent foramen ovale (PFO), previously closed muscular ventricular septal defect (VSD), severe hypotonia, global developmental delay, convergent strabismus, and feeding difficulties requiring gastrostomy. Cranial ultrasound revealed ventriculomegaly, grade II intraventricular hemorrhage, slightly thin corpus callosum, and altered posterior cranial fossa. Postnatal genetic evaluation, including array CGH (comparative genomic hybridization), conventional karyotyping, FISH (fluorescent in situ hybridization), and QF-PCR (Quantitative Fluorescence Polymerase Chain Reaction), identified a complex mosaicism comprising three cell lines: 47,XX,+del(9)(q13)[60%]/47,XX,+9[20%]/46,XX[20%]. CONCLUSION: This case expands the phenotypic spectrum of chromosome 9 mosaicism and highlights the diagnostic value of multimodal genomic analysis for accurate detection and counselling.
Genome-wide characterization of NBS-encoding genes in and their putative roles in disease resistance.
Yang X, Zeng F, Liu B … +5 more , Yang Z, Wei H, Gao J, Wang P, Liu X
Front Genet · 2026 · PMID 42017140 · Full text
Sponge gourd ( Mill.), a crucial dual-purpose crop in the Cucurbitaceae family, faces severe yield losses due to diseases like Fusarium wilt and Tomato leaf curl New Delhi virus (ToLCNDV) infection. The NBS-LRR (Nucleoti...
Sponge gourd ( Mill.), a crucial dual-purpose crop in the Cucurbitaceae family, faces severe yield losses due to diseases like Fusarium wilt and Tomato leaf curl New Delhi virus (ToLCNDV) infection. The NBS-LRR (Nucleotide-Binding Site-Leucine-Rich Repeat) gene family, core components of plant Effector-Triggered Immunity (ETI), plays a vital role in pathogen defense. This study conducted a comprehensive genome-wide analysis of the NBS-LRR gene family in using bioinformatics tools and transcriptome data. A total of 89 NBS-LRR genes were identified and classified into seven subfamilies: TIR(Toll/Interleukin-1 Receptor)-NBS-LRR(TNL) (15), TIR-NBS(TN)(16), CC (Coiled-Coil))-NBS-LRR(CNL)(8), CC-NBS (CN) (14), NBS(N)(23), NBS-LRR (NL) (10), and RN(RPW8-NBS) (3). These genes showed irregular distribution across 12 chromosomes, with the highest density on Chr08. Phylogenetic analysis revealed five primary clades, reflecting evolutionary relationships among subfamilies. Conserved domain and motif analysis indicated intra-subfamily conservation and inter-subfamily divergence, with all members containing the core NB-ARC domain. Promoter -acting element analysis identified 65 elements, with light-responsive and hormone/defense-stress-responsive elements being predominant, suggesting involvement in multiple biological processes. Intra-species synteny analysis found two homologous gene pairs between Chr02 and Chr06, while inter-species analysis showed closer evolutionary ties with cucumber (18 orthologous pairs) than (1 ortholog) and no orthologs with rice. Tissue-specific expression analysis revealed highest expression in roots, and disease response analysis identified six genes associated with ToLCNDV resistance and nine genes linked to Fusarium wilt resistance. These findings provide valuable resources for understanding the molecular basis of disease resistance in and accelerating disease-resistant breeding.
Identification and functional analysis of NAD metabolism-related gene NT5E in pulmonary hypertension.
Chu Y, Yang J, Ye T … +3 more , Yu F, Wang Q, Zhuo J
Front Genet · 2026 · PMID 42017139 · Full text
BACKGROUND: Pulmonary hypertension (PH) is a severe progressive disease characterised by elevated pulmonary vascular resistance and right ventricular hypertrophy. Increasing evidence has highlighted the vital role of nic...
BACKGROUND: Pulmonary hypertension (PH) is a severe progressive disease characterised by elevated pulmonary vascular resistance and right ventricular hypertrophy. Increasing evidence has highlighted the vital role of nicotinamide adenine dinucleotide (NAD) metabolism in cardiovascular disease. However, the role of NAD metabolism-related genes (NMRGs) in PH remains unclear. In this study, we aimed to identify novel NMRGs as biomarkers in PH. METHODS: Using the Gene Expression Omnibus database and Limma R package, we identified differentially expressed genes (DEGs) of PH and downloaded NMRGs from Kyoto Encyclopedia of Genes and Genomes and Reactome databases. Candidate NMRGs were subsequently identified by overlapping DEGs, NMRGs, and module genes obtained by weighted gene co-expression network analysis. The diagnostic value of these candidate NMRGs was evaluated using receiver operator characteristic (ROC) curve analysis, and gene set enrichment analysis (GSEA) was performed to explore the functional roles of hub genes. CIBERSORT algorithm was employed to assess immune cell infiltration in the PH microenvironment. Finally, the functional role of target genes in PH was validated through cellular experiments. RESULTS: Through comprehensive bioinformatics analyses across multiple datasets, we identified two NMRGs: NT5E and CD38. ROC analysis confirmed the higher predictive accuracy of NT5E, with area under the ROC curve values reaching 0.891 and 0.894 in GSE113439 and GSE53408 datasets, respectively. GSEA revealed that patients with high NT5E expression exhibited significant enrichment of PH-related biological functions and pathways. Given the relationship between NAD and immunity, immune infiltration analysis was performed, which showed a close association between NT5E expression and plasma cells and eosinophils in the PH microenvironment. experiments further showed that NT5E was significantly upregulated in a PH cell model, and knockdown of NT5E attenuated hypoxia-induced proliferation, resistance to apoptosis, and migratory ability of pulmonary arterial smooth muscle cells. CONCLUSION: Based on bioinformatics analysis and validation, we confirmed that NMRGs affect PH progression, with NT5E showing potential as a novel diagnostic marker and therapeutic target in PH.
Single-cell sequencing reveals the functional heterogeneity of melanoma cells and their crosstalk with the tumor microenvironment.
Qiao J, Li X, Qin Z … +5 more , Zhao P, Zhou H, Qiu L, Yuan Y, Zhong L
Front Genet · 2026 · PMID 41993933 · Full text
BACKGROUND: Cutaneous melanoma is a highly aggressive malignancy characterized by significant heterogeneity, rapid progression, and variable treatment responses. Understanding the functional diversity of melanoma cells a...
BACKGROUND: Cutaneous melanoma is a highly aggressive malignancy characterized by significant heterogeneity, rapid progression, and variable treatment responses. Understanding the functional diversity of melanoma cells and their interactions with the tumor microenvironment (TME) is crucial for developing effective therapeutic strategies and identifying prognostic biomarkers. METHODS: We performed comprehensive single-cell RNA sequencing (scRNA-seq) analysis of 70,760 cells from 11 melanoma samples. Data processing was conducted using Seurat v4.3.0 with Harmony integration. Cell-cell communication was inferred using CellChat, and pseudotime trajectory analysis was performed using Monocle 2. A prognostic model was constructed by integrating 10 machine learning algorithms within a leave-one-out cross-validation (LOOCV) framework using the TCGA-SKCM cohort. Experimental validation was performed using immunofluorescence analysis on clinical specimens from seven melanoma patients. RESULTS: We identified seven major cell types and characterized nine distinct melanoma cell subpopulations with unique molecular signatures. Notably, subpopulations Mela4, Mela6, and Mela9 demonstrated significant associations with favorable patient prognosis and exhibited the highest interaction strength with immune cells in the TME. Cell communication analysis revealed that these subpopulations primarily engaged in signaling through MIF-CD74/CD44/CXCR4 and MHC-I pathways, with CD8 T cells being the predominant signal recipients. Pseudotime trajectory analysis identified critical genes (CYR61, JUN, RHOC) involved in melanoma cell state transitions. Using an integrative machine learning approach, we developed a melanoma cell-associated signature (MRS) comprising 15 genes that achieved a mean C-index of 0.675 across validation cohorts. Furthermore, High EIF5A expression was significantly associated with poor patient outcomes (p < 0.001), Immunofluorescence analysis showing significantly elevated EIF5A expression in melanoma tissues compared to controls (p < 0.01). CONCLUSION: This study reveals the functional heterogeneity of melanoma cells and their interactions with the immune microenvironment, identifies key subpopulations, prognostic signatures, and EIF5A as a plausible prognostic biomarker candidate and potential therapeutic target that warrants mechanistic validation in melanoma.
BHLHE41-SLC7A11 transcriptional axis and chromatin remodeling signatures in osteogenic-lineage disulfidptosis-like stress in osteoporosis.
Zhao X, Xue W, Gao J … +4 more , Zhang Y, Chen J, Zhang Y, Long S
Front Genet · 2026 · PMID 41993932 · Full text
BACKGROUND: Osteoporosis (OP) is characterized by impaired bone homeostasis in which bone resorption exceeds bone formation. Disulfidptosis, a recently described disulfide stress-induced cell death program linked to cyto...
BACKGROUND: Osteoporosis (OP) is characterized by impaired bone homeostasis in which bone resorption exceeds bone formation. Disulfidptosis, a recently described disulfide stress-induced cell death program linked to cytoskeletal collapse, has been suggested to contribute to OP, yet its cell-type-specific relevance within the bone marrow mesenchymal stem cell (BM-MSC) osteogenic lineage-and the upstream upstream transcriptional and epigenetic programs shaping this stress response-remain unclear. METHODS: This study integrated a peripheral blood monocyte microarray dataset (GSE56815; 20 OP vs. 20 controls) with single-cell RNA sequencing to characterize disulfidptosis-related programs in OP. OP-associated disulfidptosis genes and molecular subtypes were identified using co-expression and differential analyses. Disulfidptosis score and upstream regulators across bone marrow cell populations were inferred from single-cell data using regulon analysis with motif/cis-regulatory evidence. Chromatin remodeling-related gene modules in osteoblasts were additionally scored to assess epigenetic activation/repression programs and their association with BHLHE41. RESULTS: Integrated WGCNA with gene-overlap screening pinpointed 17 OP-linked disulfidptosis signature genes, highlighted by a marked increase of SLC7A11, and unsupervised stratification separated OP into two molecular subtypes. Single-cell analyses showed that disulfidptosis score was enriched in the osteoblast-like subset of BM-MSCs, implicating osteoblasts as a major affected population. Network inference further nominated BHLHE41 as a potential upstream driver of SLC7A11 and connected its expression with a disulfidptosis-tolerant phenotype in OP-derived BM-MSCs. Chromatin remodeling pathway scoring indicated altered epigenetic state programs in OP osteoblasts, and SIRT1 was preferentially upregulated in BHLHE41-high osteoblasts. CONCLUSION: This study provides a cell-type-resolved map of disulfidptosis-related stress in osteoporosis by integrating bulk and single-cell transcriptomics. We propose a BM-MSC osteogenic-lineage-associated BHLHE41-SLC7A11 axis and link it to chromatin remodeling signatures in osteoblasts, offering a rationale for precision strategies targeting disulfide-stress vulnerability in OP.
Functional inactivation of MDR3 caused by a homozygous missense variant leading to liver failure.
Heinrich S, Behrendt A, Sgodda M … +7 more , Gohlke H, Auber B, Stalke A, Hartleben B, Wedemeyer H, Cantz T, Taubert R
Front Genet · 2026 · PMID 41993931 · Full text
Progressive familial intrahepatic cholestasis (PFIC) is a rare hereditary liver disorder that is caused by defective hepatobiliary transport. Variants in ATP binding cassette 4 ( ), encoding phosphatidylcholine floppase...
Progressive familial intrahepatic cholestasis (PFIC) is a rare hereditary liver disorder that is caused by defective hepatobiliary transport. Variants in ATP binding cassette 4 ( ), encoding phosphatidylcholine floppase MDR3, are a frequent cause; however, many remain classified as variants of uncertain significance (VUS), limiting molecular diagnosis. Here, we functionally characterized a previously reported homozygous missense variant (c.431G>A, p.(Arg144Gln)) without experimental evidence of pathogenicity. An analysis using the ABCB4-specific prediction tool Vasor indicated a high probability of pathogenicity (0.88). Structural modeling suggested that Arg144Gln disrupted key electrostatic interactions essential for MDR3 membrane anchoring. Immunofluorescence analyses demonstrated markedly reduced membrane localization with residual cytoplasmic retention, consistent with complete loss of protein function. In conclusion, the p.(Arg144Gln) variant causes functional inactivation of MDR3 and represents a novel pathogenic mutation. Combined genetic, structural, and functional analyses are valuable tools for characterizing variants of uncertain significance in -associated cholestatic liver disease.
Multi-omics analysis to identify the dynamic changes of immune cells and marker genes in renal fibrosis.
Yi W, Cao M, Tan X … +2 more , Du G, Li J
Front Genet · 2026 · PMID 41993930 · Full text
INTRODUCTION: Renal fibrosis is a common pathological feature of chronic kidney disease and a major driver of progression to end-stage renal disease, but its molecular mechanisms remain incompletely understood. METHODS:...
INTRODUCTION: Renal fibrosis is a common pathological feature of chronic kidney disease and a major driver of progression to end-stage renal disease, but its molecular mechanisms remain incompletely understood. METHODS: We integrated multi-omics datasets from GEO and published studies, including mRNA, protein, miRNA, and circRNA data from unilateral ureteral obstruction (UUO) models, TGF-β-induced in vitro fibrosis models, and human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Exo). Differential expression analysis, functional enrichment, immune infiltration analysis, fuzzy c-means clustering, weighted gene co-expression network analysis, and ceRNA network construction were performed, with selected findings further validated experimentally. RESULTS: We identified stable fibrosis-associated genes and proteins, with metabolic dysregulation emerging as a prominent feature of renal fibrosis. Time-series analysis revealed dynamic transcriptional changes during UUO progression. Comparative analysis showed that in vitro fibrosis models reproduced only part of the in vivo molecular landscape. Immune analyses consistently highlighted macrophages, especially M2-like macrophages, and also suggested a potential role for B cells. In addition, we identified immune-related hub genes and constructed fibrosis-associated ceRNA networks linked to macrophage regulation. Several miRNAs enriched in HucMSC-Exo, particularly miR-30a-5p, were predicted to counteract fibrosis, and exosome treatment alleviated renal injury, macrophage infiltration, and fibrotic marker expression. CONCLUSION: These findings provide a comprehensive view of the molecular and immune landscape of renal fibrosis, clarify key differences between and fibrosis models, and suggest potential therapeutic targets for antifibrotic intervention.
Serum tumor markers combined with HRCT for malignancy risk assessment of solitary pulmonary nodules: a retrospective study.
Zhou Y, Wang S, Zhang Y
Front Genet · 2026 · PMID 41988646 · Full text
INTRODUCTION: This study aims to investigate the correlation between serum tumor markers (CEA, NSE, CA-125, and CYFRA 21-1) and imaging findings in patients with solitary pulmonary nodules, and to assess their value in p...
INTRODUCTION: This study aims to investigate the correlation between serum tumor markers (CEA, NSE, CA-125, and CYFRA 21-1) and imaging findings in patients with solitary pulmonary nodules, and to assess their value in predicting the risk of malignancy. METHODS: A retrospective analysis was conducted on 110 patients with solitary pulmonary nodules, of whom 45 were benign and 65 were malignant. The clinical data, serum tumor marker levels, CT imaging findings, and diagnostic efficacy of single and combined tests were compared between the two groups. RESULTS: Serum levels of CEA, CA-125, CYFRA 21-1, and NSE in the malignant nodule group were significantly higher than those in the benign nodule group (P < 0.001). CT imaging revealed that patients with malignant nodules typically exhibited characteristics such as deep lobulation, pleural indentation, short fine spiculation, and multiple cystic lucencies, whereas the benign nodule group more commonly displayed pleural thickening and satellite lesions. The diagnostic efficacy of combined CT and tumor marker testing was significantly superior to that of single tests, with a sensitivity of 96.9% and an accuracy of 87.3%. The area under the curve (AUC) of the combined detection was significantly higher than that of any single indicator (P < 0.05). DISCUSSION: The combined detection of serum tumor markers and high-resolution CT imaging findings has high clinical value in the diagnosis of benign and malignant solitary pulmonary nodules, offering a more precise basis for cancer risk assessment.
Federated, governed, and interoperable? The emerging architecture of public human genomic data infrastructures: a European perspective.
Tangaro MA, Chiara M, Pesole G … +1 more , Zambelli F
Front Genet · 2026 · PMID 41988645 · Full text
Public infrastructures for human genomic data are increasingly incorporating federated approaches alongside centralized and cloud-native models, yet operational federation remains constrained by unsolved challenges at th...
Public infrastructures for human genomic data are increasingly incorporating federated approaches alongside centralized and cloud-native models, yet operational federation remains constrained by unsolved challenges at the legal, semantic, and technical layers. We describe the current landscape along three analytical axes, taking a primarily European perspective while drawing on global examples to highlight broader trends. First, we compare architectural models, centralized archives such as the European Genome-phenome Archive (EGA) and the database of Genotypes and Phenotypes (dbGaP), cloud-native platforms for data analysis, and federated networks exemplified by the European Genomic Data Infrastructure (GDI), highlighting their specific trade-offs on scalability, sovereignty, and analytical flexibility. Second, we examine the governance layer, from the tension between the GDPR's consent requirements and large-scale secondary use, through the European Health Data Space (EHDS) and Health Data Access Bodies, to machine-readable authorization via GA4GH Passports and the Data Use Ontology. Third, we assess interoperability and semantic alignment, including the role of GA4GH technical standards, FAIR metadata principles, and emerging schema harmonization efforts such as the German Human Genome-Phenome Archive (GHGA). We argue that the central challenge is no longer building individual platforms, but aligning heterogeneous regulatory interpretations, metadata models, and trust frameworks across jurisdictions. Addressing this alignment gap will determine whether federated genomics delivers on its promise of large-scale, privacy-preserving data reuse.
Genetic association of rs80213143 with susceptibility and renal involvement in systemic lupus erythematosus.
Zhang XX, You JP, Li YC … +6 more , Xu HD, Chen XY, Feng KL, He ZQ, Zhao ZZ, Qi YY
Front Genet · 2026 · PMID 41988644 · Full text
BACKGROUNDS: Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement, and lupus nephritis (LN) is a severe manifestation. Long non-coding RNAs (lncRNAs) have been implicated in regulating...
BACKGROUNDS: Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement, and lupus nephritis (LN) is a severe manifestation. Long non-coding RNAs (lncRNAs) have been implicated in regulating immune responses in autoimmune diseases. LOC100130476, a lncRNA located on chromosome 6q23.3, has been linked to inflammation and cancer progression, but its role in SLE and LN remains unclear. METHODS: We studied the association between the rs80213143 variant at LOC100130476 and SLE susceptibility in a Chinese Han cohort, using SNP genotyping and Bonferroni correction for multiple comparisons. Functional annotations were conducted to explore the effects of rs80213143 on transcription factor binding and gene expression. eQTL analysis was performed to assess the variant's impact on immune cell gene expression. RESULTS: Within LOC100130476, the strongest association was observed at rs80213143 (p = 2.5 × 10), which was successfully replicated (p = 2.64 × 10) in an independent cohort. The combined analysis of both discovery and replication cohorts reinforced the genetic association (p = 2.04 × 10). The risk C allele was linked to more severe renal involvement, including higher 24-h proteinuria and serum creatinine levels. Functional annotations indicated that rs80213143 potentially influences immune cell functionality through regulatory motif alterations. The expression of was abnormally upregulated in the whole blood of SLE patients, particularly in lupus nephritis patients. Moreover, the expression of was significantly upregulated in the biopsy samples of lupus nephritis patients. Differentially expressed genes in whole blood between SLE patients and healthy donors, positively associated with expression, were significantly enriched in pathways involving T cell receptor signaling, antigen presentation, interferon response, and apoptosis. Furthermore, showed positive associations with genes differentially expressed between LN patients' renal biopsy tissues and adjacent normal renal tissues, enriched in leukocyte-mediated immunity, inflammatory responses, extracellular matrix and tissue repair pathways, and the PI3K signaling network. CONCLUSION: The rs80213143 variant in LOC100130476 is associated with SLE susceptibility and renal involvement. Its elevated expression in lupus nephritis suggests it may be an important factor in disease pathogenesis and a potential biomarker for lupus nephritis.
TTN variants in pediatric cardiomyopathy: a retrospective cohort study.
Qiu Y, Liu L, Zhou K … +2 more , Li Y, Hua Y
Front Genet · 2026 · PMID 41988643 · Full text
BACKGROUND: Titin (TTN) variants have been implicated in various types of cardiomyopathy. Allelic variant heterogeneity results in variable clinical phenotypes, which remains a major barrier for effective disease managem...
BACKGROUND: Titin (TTN) variants have been implicated in various types of cardiomyopathy. Allelic variant heterogeneity results in variable clinical phenotypes, which remains a major barrier for effective disease management. We aim to investigate the relationship between variants and their associated cardiomyopathies and clinical outcomes. METHODS: A retrospective observational study was performed to evaluate patients with cardiomyopathy and variants confirmed by whole-exome sequencing (WES) from January 2015 to December 2024. Univariable Cox regression analysis was conducted to identify independent risk factors for major adverse cardiovascular events (MACEs), and receiver operating characteristic analysis was used to determine its capability. In addition, the contribution of combined pathogenic variants with the TTN gene was assessed. RESULTS: A total of 53 patients were identified with TTN variants, with a , while 48 of 53 (90.50%) individuals had other genetic variants. Among them, 47.17% of patients presented with recurrent heart failure, while late gadolinium enhancement (LGE) was identified in 56.67% of cases that underwent magnetic resonance imaging (MRI) assessment. The variants in the A-band of were most frequently recorded among the patients. Notably, early age-onset disease (HR = 1.008; 95% CI = 1.000-1.016; = 0.037) served as a predictor of MACE in pediatrics with -associated cardiomyopathy, and the optimal cutoff value was calculated as 75.50 months (specificity 57.1% and sensitivity 75.0%). Unfortunately, the combined genetic disorders failed to establish an association with worse outcomes in the general cohort. However, specifically in patients with dilated cardiomyopathy (DCM), with a higher prevalence of MACE occurrence. CONCLUSION: In our cohort, early age-onset disease was a predictor of MACE in pediatrics with -associated cardiomyopathy. In addition, the early age of disease onset revealed a higher likelihood of MACE in the first year after diagnosis. Multiple genetic variants with presented more severe adverse outcomes in DCM assessment.
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