Frontiers in Genetics最新文献

{"title":"Analysis of follow-up data in large biobank cohorts: a review of methodology.","authors":"Anastassia Kolde, Merli Koitmäe, Meelis Käärik, Märt Möls, Krista Fischer","doi":"10.3389/fgene.2025.1534726","DOIUrl":"10.3389/fgene.2025.1534726","url":null,"abstract":"<p><p>This study focuses on key methodological challenges in genome-wide association studies (GWAS) of biobank data with time-to-event outcomes, analyzed using the Cox proportional hazards (CPH) model. We address four primary issues: left-truncation of the data, computational inefficiency of standard model-fitting algorithms, relatedness among individuals, and model misspecification. To manage left-truncation, the common practice is to use age as the timescale, with individuals entering the risk set at their age of recruitment. We assess how this choice of timescale influences bias and statistical power, under realistic GWAS conditions of varying effect sizes and censoring rates. In addition, to alleviate the computational burden typical in large-scale data, we propose and evaluate a two-step martingale residual (MR) approach for high-dimensional CPH modeling. Our results show that the timescale choice has minimal effect on accuracy for small hazard ratios, though using time since birth as the timescale - ignoring recruitment age - yields the highest power for association detection. We find that relatedness, when ignored, does not substantially bias effect size estimates, while omitting key covariates introduces significant bias. The two-step MR approach proves to be computationally efficient, retaining power for detecting small effect sizes, making it suitable for large-scale association studies. However, when precise effect size estimates are critical, particularly for moderate or larger effect sizes, we recommend recalculating these estimates using the conventional CPH model, with careful attention to left-truncation and relatedness. These conclusions are drawn from simulations and illustrated with data from the Estonian Biobank cohort.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1534726"},"PeriodicalIF":2.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Genetic landscape of hypertrophic cardiomyopathy in Hong Kong Chinese population.","authors":"Derek P H Lee, Ye Cao, Lilei Zhang","doi":"10.3389/fgene.2025.1641043","DOIUrl":"https://doi.org/10.3389/fgene.2025.1641043","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fgene.2025.1583838.].</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1641043"},"PeriodicalIF":2.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of chromosome microarray analysis and karyotyping in fetal cardiac abnormalities.","authors":"Yun Guo, Xiaoqin Xin, Linju Zhou, Jungao Huang","doi":"10.3389/fgene.2025.1611388","DOIUrl":"10.3389/fgene.2025.1611388","url":null,"abstract":"<p><strong>Objective: </strong>Chromosome microarray analysis (CMA) and karyotyping are two important genetic testing techniques used in prenatal diagnosis. This study aims to evaluate the value of chromosome microarray analysis and karyotyping in the diagnosis of fetal cardiac abnormalities, with particular focus on the detection of genomic copy number variations (CNVs).</p><p><strong>Methods: </strong>A retrospective analysis was conducted on 98 pregnant women diagnosed with fetal cardiac abnormalities through ultrasound between January 2022 and June 2024. Amniotic fluid samples from all participants were subjected to the analysis of karyotyping and Chromosome microarray analysis. The detection rates of both techniques in different types of fetal cardiac abnormalities were compared, and the outcomes of positive cases were followed up.</p><p><strong>Results: </strong>Of the 98 fetuses with cardiac abnormalities, 12 cases showed abnormal genetic results, with a detection rate of 12.24%. Karyotyping identified 5 cases of abnormalities (5.10%), while the chromosome microarray analysis detected 11 cases (11.22%). In the group with isolated cardiac abnormalities (76 cases) and the group with cardiac abnormalities combined with other ultrasound abnormalities (22 cases), karyotyping detected 3.95% (3/76) and 9.09% (2/22) of abnormalities, with no significant statistical difference (P > 0.05). Chromosome microarray analysis detected abnormalities in 6.58% (5/76) of the isolated cardiac abnormalities group and 27.27% (6/22) in the group with combined abnormalities, showing a significant statistical difference (P < 0.05). Of the 12 positive cases, four were live births, eight were terminations, and <i>postpartum</i> cardiac abnormalities were found in two live births during follow-up.</p><p><strong>Conclusion: </strong>Chromosome microarray analysis has a higher detection rate in fetuses with cardiac abnormalities than traditional chromosome karyotyping, especially when fetal cardiac abnormalities are combined with other ultrasound abnormalities. It is recommended for clinical use to improve the detection of genetic alterations.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1611388"},"PeriodicalIF":2.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12237624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of the interaction between occupational hazard factors and IL-1β gene polymorphism with cognitive function in electrolytic aluminum workers.","authors":"Youxing Li, Yaqin Pang, Dongshun Chen, Feiyu Lu, Hongyan Tian, Fengni Qin, Kuntao Wei, Ahmad Razali Bin Ishak, Mohd Shukri Bin Mohd Aris, Guangzi Qi","doi":"10.3389/fgene.2025.1591908","DOIUrl":"10.3389/fgene.2025.1591908","url":null,"abstract":"<p><strong>Background: </strong>Various occupational hazards in the electrolytic aluminum environment have been linked to cognitive decline. However, the interactive effects of these hazards and genetic factors on cognitive function remain unclear.</p><p><strong>Objective: </strong>This study aimed to identify the primary occupational hazards, examine their interaction with IL-1β gene polymorphisms in relation to cognitive function.</p><p><strong>Methods: </strong>A cross-sectional study was conducted in June 2024 at an electrolytic aluminum company in China, involving 478 male workers. Cognitive function was assessed using the Montreal Cognitive Assessment. Calculate the cumulative exposure dose of harmful factors such as aluminum dust. Additionally, IL-1β gene polymorphisms (rs1143627, rs1143643, rs16944, rs3917356) and serum protein levels were analyzed. The associations between environmental exposure, genetic factors, and cognitive function were examined using multivariate stepwise linear regression, restricted cubic splines, generalized linear models, and hierarchical analysis. Covariance analysis and independent sample t-tests were employed to assess the potential mediating effect of peripheral blood IL-1β levels.</p><p><strong>Results: </strong>Cumulative exposure to aluminum dust was significantly associated with cognitive decline (β = -0.18, 95% CI: 0.27, -0.10), and the relationship was linear. Compared to the wild genotype, individuals carrying rs1143627 G/G, rs1143643 C/C, and rs16944 A/A exhibited significantly lower cognitive scores (<i>P</i> < 0.01), whereas rs3917356 C/T and T/T conferred a protective effect (<i>P</i> < 0.01). The model was adjusted for age, body mass index, and cumulative aluminum dust exposure. The genetic effect associated with IL-1β was more pronounced in individuals with high aluminum exposure (>2.37 mg/m³ × year). IL-1β serum protein levels showed no significant association with cognitive function (<i>P</i> > 0.05).</p><p><strong>Conclusion: </strong>Cumulative exposure to aluminum dust is a key risk factor for cognitive decline. IL-1β polymorphisms influence susceptibility, with the effect becoming more pronounced under high aluminum exposure. However, peripheral blood IL-1β levels do not mediate this association with cognitive decline.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1591908"},"PeriodicalIF":2.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12237639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A machine learning framework for predicting cognitive impairment in aging populations using urinary metal and demographic data.","authors":"Fengchun Ren, Xiao Zhao, Qin Yang, Huaqiang Liao, Yudong Zhang, Xuemei Liu","doi":"10.3389/fgene.2025.1631228","DOIUrl":"10.3389/fgene.2025.1631228","url":null,"abstract":"<p><strong>Introduction: </strong>Cognitive impairment in older adults poses a significant global public health concern, with environmental metal exposure emerging as a major risk factor. However, the combined effects of multiple metals and the modulatory roles of demographic variables remain insufficiently explored.</p><p><strong>Methods: </strong>This study analyzed data from four NHANES cycles (1999-2000, 2001-2002, 2011-2012, 2013-2014), comprising 1,230 participants aged ≥ 60 years. Urinary concentrations of nine metals and creatinine were quantified in conjunction with demographic variables. Cognitive status was classified using data-driven quartile thresholds on the Digit Symbol Substitution Test, CERAD Word-Learning Test, and Animal Fluency tests. Six machine learning algorithms were trained and evaluated using sensitivity (SN), specificity (SP), accuracy (ACC), Matthews correlation coefficient (MCC) and AUC.</p><p><strong>Results: </strong>The eXtreme gradient boosting (XGBoost) model demonstrated superior performance across all metrics (SN = 0.78, SP = 0.84, ACC = 0.81, MCC = 0.62, AUC = 0.90), and was selected for subsequent interpretation. SHAP analysis identified educational level, age, race/ethnicity, and creatinine as primary predictors. Elevated thallium and molybdenum levels and reduced barium levels also contributed to cognitive risk. Ultimately, a user-friendly webserver was deployed for the predictive model and is freely accessed at http://bio-medical.online/admxp/.</p><p><strong>Discussion: </strong>The associated webserver enables accessible risk screening and underpins precision prevention strategies in aging populations.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1631228"},"PeriodicalIF":2.8,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12237647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared genetic loci connect cardiovascular disease with blood pressure and lipid traits in East Asian populations.","authors":"Peng Zhong, Chumeng Zhang, Qinfeng Wu, Xiao Chang","doi":"10.3389/fgene.2025.1635378","DOIUrl":"10.3389/fgene.2025.1635378","url":null,"abstract":"<p><strong>Introduction: </strong>Cardiovascular diseases (CVDs), including myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and arrhythmia, are major contributors to global mortality and often share overlapping risk factors and pathophysiological mechanisms. While genome-wide association studies (GWAS) have identified many loci for individual CVDs, the shared genetic architecture across related traits-particularly in East Asian populations-remains underexplored.</p><p><strong>Materials and methods: </strong>We integrated large-scale GWAS summary statistics from East Asian populations to perform genome-wide and local genetic correlation analyses across four CVD phenotypes and five cardiometabolic traits (blood pressure and lipid levels). Using stratified LD score regression, we assessed tissue-specific heritability enrichment. Multi-trait analysis of GWAS (MTAG) was then employed to identify pleiotropic loci associated with multiple traits, with functional annotation and expression quantitative trait loci (eQTL) data used to explore biological relevance.</p><p><strong>Results: </strong>We observed extensive genetic correlations among CVDs and between CVDs and cardiometabolic traits, with HF showing the strongest connections to both MI and arrhythmia. Notable genome-wide correlations were found between MI and SBP (rg = 0.35, <i>P</i> = 1.59 × 10^-14) and between HF and DBP (rg = 0.54, <i>P</i> = 9.84 × 10^-9). Stratified heritability analyses revealed significant enrichment in heart and arterial tissues, highlighting the relevance of cardiovascular-specific regulatory elements. MTAG identified several pleiotropic loci, including established genes such as <i>APOB</i> and <i>MC4R</i>, and novel East Asian-enriched signals such as <i>QSOX2</i> and <i>GUCY1A1</i>/<i>GUCY1B1</i>. Functional data indicated that <i>QSOX2</i> variants regulate gene expression in arterial and cardiac tissues, implicating redox regulation in HF and hypertension pathogenesis.</p><p><strong>Conclusion: </strong>Our findings provide comprehensive insight into the shared genetic determinants of cardiovascular and metabolic diseases in East Asian populations. The identification of pleiotropic and ancestry-specific loci, along with tissue-specific regulatory patterns, underscores the need for integrative multi-trait and population-informed approaches in cardiovascular genetics and risk prediction.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1635378"},"PeriodicalIF":2.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene polymorphisms associated with immunosuppressant adverse effects in systemic lupus erythematosus: a narrative review.","authors":"Siva Hamdani, Laniyati Hamijoyo, Riezki Amalia, Melisa I Barliana","doi":"10.3389/fgene.2025.1594648","DOIUrl":"10.3389/fgene.2025.1594648","url":null,"abstract":"<p><p>Systemic Lupus Erythematosus (SLE) is an autoimmune disease that often requires treatment with immunosuppressant drugs to manage symptoms and prevent organ damage. However, the use of immunosuppressant can be associated with various adverse effects. The spectrum of immunosuppressant toxicity is influenced by various factors such as organ function and medication interval, but genetic variations-particularly single nucleotide polymorphisms-have emerged as critical determinants due to their direct impact on the drug's pharmacokinetics and pharmacodynamics alteration, also on patient susceptibility to adverse reactions. This review summarizes the current knowledge on gene polymorphisms associated with immunosuppressant adverse effects in SLE patients, focusing on commonly used drugs such as Methotrexate (MTX), Azathioprine (AZA), Cyclophosphamide (CYC), and Mycophenolate Mofetil (MMF). A total of 23 relevant studies published in the last decade were identified through a comprehensive literature search, specifically investigating the relationship between gene polymorphisms and adverse drug reactions in SLE patients. The findings reveal that gene polymorphisms are frequently associated with adverse effects for each immunosuppressant, including MTX (<i>MTHFR</i> and <i>ATIC</i>), AZA (<i>TPMT, NUDT15, ITPA, ABCC4</i>), CYC (<i>CYP2C19, GSTM1, GSTT1, GSTP1, ALDH</i>), and MMF (<i>SLCO1B1, IMPDH1, UGT2B7</i>). Understanding the functional implications of these gene polymorphisms contributes to the application of precision medicine, as they can serve as potential markers for drug selection and dosage adjustment during initiation treatment of immunosuppressant to enhance treatment efficacy, minimize toxicity, and improve outcomes for SLE patients.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1594648"},"PeriodicalIF":2.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of the <i>MUC5B</i> promoter polymorphism with idiopathic pulmonary fibrosis in a lebanese cohort.","authors":"Antoine Mouawad, Eliane Chouery, Alain Chebly, Nabiha Salem, Sandra Corbani, Maissa Safieddine, Georges Dabar","doi":"10.3389/fgene.2025.1544864","DOIUrl":"10.3389/fgene.2025.1544864","url":null,"abstract":"<p><strong>Background and objective: </strong>Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease that causes irreversible alterations in the architecture of the lung parenchyma, leading to impaired ventilation. Both environmental factors and genetic predisposition play significant roles in the development of IPF. A single nucleotide polymorphism (SNP) (rs35705950) within the promoter of the mucin 5B gene (<i>MUC5B)</i> has been reported to be associated with the disease; however, no data is available from Lebanon or the Middle East. This study aims to identify the frequency of the <i>MUC5B</i> promoter variant among a cohort of Lebanese IPF patients, compare it to the general population and assess its association with the risk of developing the disease.</p><p><strong>Methods: </strong>A total of 55 patients diagnosed with IPF, according to the ATS/ERS criteria, and 94 healthy controls were included in the study. DNA samples were extracted and genotyped for the <i>MUC5B</i> promoter polymorphism by Sanger sequencing. Descriptive statistics were performed on clinical characteristics. Pearson's chi-squared and T-student tests were performed to determine statistical significance. Odds ratios quantified genetic variant associations with IPF.</p><p><strong>Results: </strong>The <i>MUC5B</i> SNP rs35705950 was significantly more frequent in IPF patients compared to the control group, in both heterozygous and homozygous forms. Additionally, a significant association was found between the variant and susceptibility to IPF.</p><p><strong>Conclusion: </strong>This study shows that the <i>MUC5B</i> polymorphism rs35705950 is significantly more frequent in the Lebanese IPF population compared to the control group and is associated with an increased risk of developing IPF.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1544864"},"PeriodicalIF":2.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Novel truncating PPM1D variant in a dichorionic diamniotic (DCDA) twin with Jansen-de Vries syndrome. an updated perspective.","authors":"Francisco Javier Merida De la Torre, Javier Porta Pelayo, Inmaculada Ortiz-Martín","doi":"10.3389/fgene.2025.1601752","DOIUrl":"10.3389/fgene.2025.1601752","url":null,"abstract":"<p><strong>Introduction: </strong>Jansen-de Vries syndrome (JDVS) is a rare autosomal dominant neurodevelopmental disorder caused by truncating variants in exons 5 and 6 of the <i>PPM1D</i> gene. Its diagnosis is often delayed due to symptom overlap with more common conditions such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). This case report highlights the unique presentation of JDVS in one of a pair of dichorionic diamniotic (DCDA) twin brothers, both with ASD/ADHD, underscoring the diagnostic value of genetic testing.</p><p><strong>Case presentation: </strong>A 6-year-old boy presented with delayed language development, learning difficulties, behavioral issues, restrictive eating, and impaired autonomy. His twin brother, although also diagnosed with ASD/ADHD, exhibited milder symptoms. Trio-whole-exome sequencing revealed a <i>de novo</i> frameshift mutation (c.1411_1412del) in <i>PPM1D</i> in the proband, classified as pathogenic. The brother had no such variant.</p><p><strong>Interventions and outcomes: </strong>The proband received multidisciplinary interventions including behavioral therapy and speech support. Follow-up showed improvements in language, sleep, and academic performance, though behavioral and sphincter issues persist. The twin without the mutation was discharged from mental health services, while his brother remains under annual review.</p><p><strong>Conclusion: </strong>This case emphasizes the expanding phenotypic spectrum of JDVS and illustrates the diagnostic value of trio-WES in neurodevelopmental disorders with overlapping features. It also highlights the potential for discordant phenotypic expression in twins and the need for individualized diagnostic assessment.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1601752"},"PeriodicalIF":2.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An analysis of gene expression profiles through machine learning uncovers the new diagnostic signature for diabetic foot ulcers.","authors":"Yingnan Li, Ning Xiao, Zhuoqun Wang, Wenhai Wang, Fengjiao Li, Jiren Wang","doi":"10.3389/fgene.2025.1620749","DOIUrl":"10.3389/fgene.2025.1620749","url":null,"abstract":"<p><strong>Purpose: </strong>Diabetic foot ulcers (DFUs), a serious diabetes complication, greatly increase disability and mortality, underscoring the need for effective diagnostic markers.</p><p><strong>Methods: </strong>We used GSE199939 and GSE134431 datasets from the Gene Expression Omnibus (GEO) database, removed batch effects, and identified differentially expressed genes (DEGs). The weighted gene co-expression network analysis (WGCNA) was used to identify co-expression modules, followed by the integration of the protein-protein interaction (PPI) network to screen key genes, which were further optimized using LASSO regression. The gene set enrichment analysis (GSEA) analyzed key gene-related pathways, CIBERSORT assessed immune infiltration, and potential target drugs were predicted using the DGIdb database.</p><p><strong>Results: </strong>We identified 403 DEGs in DFUs, intersected them with 2,342 genes from a DFU-related WGCNA module to find 193 overlapping genes, and screened candidates via PPI network. LASSO regression finalized <i>DCT</i>, <i>PMEL</i>, and <i>KIT</i> as the key genes. GSEA analysis showed these three genes may influence the MAPK and PI3K-Akt pathways and were positively correlated with Dendritic. cells.resting. Drug target prediction identified 85 potential drugs for <i>KIT</i>, six for <i>DCT</i>, and six for <i>PMEL</i>.</p><p><strong>Conclusion: </strong>This research highlights <i>DCT</i>, <i>PMEL</i>, and <i>KIT</i> as diagnostic biomarkers for DFUs, which are linked to melanin production and the MAPK/PI3K-Akt signaling pathways.</p>","PeriodicalId":12750,"journal":{"name":"Frontiers in Genetics","volume":"16 ","pages":"1620749"},"PeriodicalIF":2.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144591099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}