Clinical Epigenetics最新文献

{"title":"Identification of macrophage polarization-related genes for esophageal cancer risk: a multi-omics Mendelian randomization analysis.","authors":"Mumu Shi, Renshi Zhou, Bo Yu, Futian Yu, Jinghai Gao","doi":"10.1186/s13148-026-02171-4","DOIUrl":"10.1186/s13148-026-02171-4","url":null,"abstract":"<p><strong>Background: </strong>This study aims to identify macrophage polarization (MP)-related genes implicated in esophageal cancer (EC) by integrating methylation quantitative trait loci (mQTL), expression QTL (eQTL), and protein QTL (pQTL) data with EC genome-wide association study (GWAS) data.</p><p><strong>Methods: </strong>GWAS data were obtained from the UK Biobank for discovery and the FinnGen R10 release for validation. Blood-based mQTL, eQTL, and pQTL summary data were sourced from large European cohorts. Summary Data-based Mendelian Randomization (SMR) analysis assessed the associations between MP-related gene methylation, expression, protein abundance, and EC risk. Colocalization analysis identified shared causal variants.</p><p><strong>Results: </strong>SMR and colocalization analysis identified 54 methylation loci, seven genes, and one protein associated with EC risk. Based on multi-omics integration and tiered evidence, LEP was classified as tier 1 due to its significant negative association in integrated mQTL-eQTL data. LEP (cg13454199) methylation showed a positive association with EC risk, while LEP expression was negatively associated, indicating that increased LEP methylation may downregulate its expression, potentially raising EC risk. INPP5D and PGF were tier 2 genes due to their associations with EC risk at both methylation and expression levels, with strong colocalization (PPH4 > 0.5). Tier 3 genes SPP1 and USP18 were associated with EC risk at single regulatory levels (protein and methylation, respectively) in the discovery cohort, with colocalization evidence and validation in an independent dataset, respectively.</p><p><strong>Conclusion: </strong>We identified LEP, INPP5D, PGF, SPP1, and USP18 as key MP-related genes associated with EC risk, providing potential therapeutic targets for EC.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13463415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation signatures of inflammation in youth living with perinatally-acquired HIV.","authors":"Stephanie Shiau, Sean S Brummel, Junjie Hu, Jasmine Douglas, Francesca Zumpano, Michael Corley, Jennifer Jao, Murli Purswani, Kunjal Patel, Carmen J Marsit","doi":"10.1186/s13148-026-02148-3","DOIUrl":"10.1186/s13148-026-02148-3","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic modifications may illuminate mechanisms by which HIV and antiretroviral therapy (ART) exposure during critical developmental periods affect biological pathways and chronic comorbidity risk. We examined genome-wide DNA methylation (DNAm) in youth with perinatally-acquired HIV (YPHIV) compared to perinatally HIV-exposed uninfected youth (YPHEU) at two timepoints. In YPHIV, we assessed associations of HIV RNA viral load, CD4 count, and inflammation with DNAm alterations.</p><p><strong>Methods: </strong>Genome-wide DNAm was measured in peripheral blood mononuclear cells from 32 YPHIV and 7 YPHEU at two timepoints separated by at least 3 years via the PHACS Adolescent Master Protocol. Differentially methylated CpG sites were evaluated genome-wide (FDR p < 0.05 and ≥ 5% methylation difference) and across 15 pre-selected targeted genes at each timepoint. Regional and pathway enrichment analyses were conducted. Among YPHIV, genome-wide associations of HIV viral load, CD4 count, and inflammation markers with DNAm were assessed.</p><p><strong>Results: </strong>No genome-wide differentially methylated CpG sites were identified between YPHIV and YPHEU at either timepoint. For targeted genes, CpG sites on PSMB9 were differentially methylated at both timepoints. Among YPHIV, neither viral load nor CD4 count was associated with DNAm. In contrast, C-reactive protein was associated with 17 and 18 CpG sites at timepoints 1 and 2, respectively, with 7 overlapping genes, including two involved in blood pressure regulation and kidney function. Interleukin-6 was associated with 3 and 2 CpG sites at timepoints 1 and 2, respectively, with 2 overlapping genes involved in fatty acid metabolism and neuronal signaling.</p><p><strong>Conclusion: </strong>Markers of inflammation were associated with DNA methylation signatures in YPHIV during childhood/adolescence. These epigenetic signatures may provide insight into the inflammatory pathways that contribute to chronic comorbidity risk in YPHIV and suggest inflammation as a potential target for early intervention.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive epigenetic biomarkers of successful weight-loss intervention in pre-pubertal children with obesity.","authors":"Flavio Palmieri, Pol Castellano-Escuder, Marcela Parra-Vargas, Maria Jesus Leal-Witt, Marta Ramón Krauel, Carles Lerin, Alexandre Perera, Josep C Jiménez-Chillarón","doi":"10.1186/s13148-026-02104-1","DOIUrl":"10.1186/s13148-026-02104-1","url":null,"abstract":"<p><p>Childhood obesity represents a major public health challenge, increasing long-term risks such as type 2 diabetes and cardiovascular disease. Lifestyle interventions in prepubertal children are often more effective, but individual responses can vary, highlighting the need for predictive biomarkers to personalize treatment. This study investigated DNA methylation profiles in prepubertal children living with obesity to identify possible epigenetic markers that could predict the success of weight loss interventions. We analyzed a cohort of 26 children who underwent a six-month lifestyle intervention focused on dietary modifications. From 214 differentially methylated CpG sites between high and low responders, we narrowed these to eight key markers. These markers were used to develop a predictive model with a precision 84% in classifying children based on their BMI normalized to changes in the z-score of the age. CpGs were found in genes such as GSDMD, GFRA1 and NRP2, all linked to pathways involved in inflammation, metabolic regulation, and lipid metabolism, which are crucial in the development of obesity. The results suggest that DNA methylation signatures can predict weight loss responses in prepubertal children, offering a novel approach to early-stage obesity intervention. These findings hold promise for the development of personalized treatment strategies in pediatric obesity. However, larger and more diverse cohort studies are needed to confirm the generalizability of these markers and refine the predictive model for broader clinical use.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13220482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-specific epigenetic effects on cardiovascular health.","authors":"Yuetong Huang, Ziyu Yang, Zhiyi Chu, Zheng Zhang, Xinyue Huang, Chengze Zheng, Yifan Chen, Jun Pu","doi":"10.1186/s13148-026-02169-y","DOIUrl":"10.1186/s13148-026-02169-y","url":null,"abstract":"<p><p>Exercise is widely prescribed to prevent cardiovascular disease, which encompasses a heterogeneous spectrum of disorders involving vascular dysfunction, myocardial injury and remodeling, inflammation, and electrophysiological disturbances; however, its benefits are not uniformly dose-dependent. While aerobic and resistance training generally elicit sustained cardioprotective adaptations, evidence from ultra-endurance exercise suggests a distinct physiological regime in which repeated extreme load, prolonged duration and individual susceptibility may precipitate maladaptive remodeling. Here we synthesize an epigenetic remodeling framework to reconcile these divergent outcomes and to explain how exercise modality, intensity and exposure duration may influence the balance between cardiovascular adaptation and vulnerability. We systematically examine epigenetic pathways, including DNA methylation, histone modifications and non-coding RNA-mediated regulation, through which aerobic exercise and resistance training may modulate vascular function, myocardial metabolism, inflammation and fibrosis. We then contrast these signatures with those reported in ultra-endurance settings, highlighting mechanistic patterns associated with transient myocardial damage markers, arrhythmogenic substrates and adverse structural remodeling in susceptible individuals. We further discuss emerging sex-specific epigenetic mechanisms that may contribute to differential cardiovascular disease trajectories under ultra-high-intensity endurance stress. Finally, we outline key limitations in current evidence, including incomplete causal epigenetic chains, heavy reliance on experimental models, peripheral tissues and elite athlete cohorts, limited tissue-specific evidence and a paucity of longitudinal population studies. Addressing these gaps will be essential for translating epigenetic insights into risk-stratified and individualized exercise prescriptions that maximize cardioprotection while minimizing potential risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13412309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148053096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic ageing during the COVID-19 pandemic: global age acceleration, independent of SARS-CoV-2 infection.","authors":"Christopher J Shore, Marc F Österdahl, Nicholas R Harvey, Naisi Zhao, Mark Kristiansen, Dominique S Michaud, Claire J Steves, Jordana T Bell, Emma L Duncan","doi":"10.1186/s13148-026-02089-x","DOIUrl":"10.1186/s13148-026-02089-x","url":null,"abstract":"<p><strong>Introduction: </strong>The COVID-19 pandemic had profound effects for both infected and uninfected individuals. We aimed to identify acute and chronic epigenetic alterations from SARS-CoV-2 infection and/or lockdown measures.</p><p><strong>Methods: </strong>Both infected and uninfected participants from the TwinsUK cohort (n = 139) provided longitudinal whole-blood samples (Spring 2020, Spring 2021). Cross-sectional and longitudinal DNA methylome [DNAm] changes, including epigenetic ageing clocks, were assessed, and EWAS (Epigenome-Wide Association Studies) were performed. Changes in epigenetic ageing clocks were compared with longitudinal samples from an independent pre-pandemic cohort (n = 35, Nurses' Health Study II cohort), assessed similarly.</p><p><strong>Results: </strong>Irrespective of SARS-CoV-2 infection, all individuals exhibited accelerated ageing from 2020 to 2021 (GrimAge clock age acceleration: p-value = 0.002, β = 0.99). In contrast, epigenetic data from paired samples from a separate pre-pandemic cohort, over a similar time period and assessed similarly, did not exhibit GrimAge acceleration. Epigenetic ageing did not differ between infected and uninfected individuals, or between recent and distant SARS-CoV-2 infection. Lastly, EWAS identified several putative changes in DNAm associated with recent, and distant, SARS-CoV-2 infection.</p><p><strong>Conclusions: </strong>Our longitudinal results suggest that the pandemic accelerated epigenetic ageing rates, irrespective of recent or distant SARS-CoV-2 infection.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic-Metabolic interplay in chronic kidney disease mortality: insights from grimage acceleration and transcriptomic profiling.","authors":"Xiangyun Dang, Zhongxin Jin, Yafeng Zhao, Yu Wang, Xiancheng Li, Xiaoyuan Liu, Pei Yan, Wei Xu, Yuhui Liu, Xiaoyong Yu, Nan Zhang","doi":"10.1186/s13148-026-02071-7","DOIUrl":"10.1186/s13148-026-02071-7","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is associated with a substantially elevated risk of mortality. Although GrimAge acceleration (GAA) and metabolic syndrome (MetS) are both implicated in this risk, their combined impact and the underlying biological mechanisms remain poorly understood.</p><p><strong>Methods: </strong>This study integrated data from National Health and Nutrition Examination Survey (NHANES; n = 2,529), Gene Expression Omnibus (GEO), and public aging-related genes. Participants with CKD were divided into four groups: low GAA without MetS (reference), high GAA without MetS (GAA), low GAA with MetS (MetS), and high GAA with MetS (GAA-MetS). Weighted Cox proportional hazards models were used to evaluate associations with all-cause mortality. Independent transcriptomic analyses of CKD (GSE66494), MetS (GSE98895) and aging-related genes datasets included differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning (LASSO and SVM-RFE) to identify hub genes. Immune cell infiltration was estimated using CIBERSORT.</p><p><strong>Results: </strong>Patients with CKD in the GAA (HR = 2.331, 95% CI: 1.785-3.043, p < 0.001), MetS (HR = 1.314, 95% CI: 1.057-1.635, p = 0.014), and GAA-MetS (HR = 2.112, 95% CI: 1.525-2.927, p < 0.001) groups exhibited significantly higher mortality risks compared to the reference group. High GAA (HR = 2.083, 95% CI: 1.533-2.831, p < 0.001) independently predicted mortality in patients aged ≥ 72 years. Sex subgroup analyses revealed elevated risks for males in both the GAA (HR = 2.440, 95% CI: 1.471-4.048, p < 0.001) and GAA-MetS (HR = 2.320, 95% CI: 1.395-3.859, p = 0.001) groups, and for females in the GAA-MetS group (HR = 1.763, 95% CI: 1.054-2.950, p = 0.031). Transcriptomic analysis identified five hub genes (ZMPSTE24, RELB, STAT6, DKC1, E2F3) implicated in CKD pathogenesis, cellular senescence, and metabolic pathways, whose expression profiles were correlated with distinct alterations in immune cell infiltration within CKD tissues.</p><p><strong>Conclusion: </strong>GAA is an independent predictor of all-cause mortality in CKD. The GAA-MetS identifies a particularly high-risk phenotype. Complementary transcriptomic analyses offer a testable hypothesis for the interplay between epigenetic and metabolic dysregulation of CKD pathogenesis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A visual analysis of the research dynamics of biomarkers for lung cancer screening.","authors":"Huange Zhu, Burong Li, Ranran Kong, Jun Yang, Zeqi Guo, Jiafeng Yin","doi":"10.1186/s13148-026-02084-2","DOIUrl":"10.1186/s13148-026-02084-2","url":null,"abstract":"<p><strong>Background: </strong>Non-invasive biomarkers offer potential to improve risk stratification and early diagnosis of lung cancer, complementing low-dose computed tomography (LDCT) screening. This study employed bibliometric analysis to identify global research trends, collaborative networks, and future directions in lung cancer biomarker research. Publications on lung cancer biomarkers for screening were retrieved from the Web of Science Core Collection (WoSCC). Data processing and visualisation were performed using Citespace, VOSviewer, KH Coder, Latent Dirichlet Allocation (LDA) topic modelling, and the online bibliometric analysis platform. Burst detection analysis was performed to predict emerging research trends.</p><p><strong>Results: </strong>Analysis of 3636 publications revealed exponential growth in research output since 2014. International collaboration demonstrated a dual-core structure centred on China and the United States, with Chinese institutions showing high publication volumes and American institutions demonstrating greater citation influence. Journal citation mapping revealed three evolutionary phases: basic mechanisms-clinical translation-intelligent integration. LDA topic modelling identified 22 topics grouped into five core research directions: imaging and pathological diagnostic techniques; molecular and omics marker research; liquid biopsy and new detection technologies; clinical and translational medicine research; and tumour biology and treatment mechanisms. Burst detection analysis predicted future four priority areas: epigenetic studies centred on DNA methylation for risk prediction; treatment resistance and invasion mechanisms; liquid biopsy technology development; and targeted therapy clinical trials.</p><p><strong>Conclusions: </strong>Lung cancer biomarker research has evolved towards multimodal, intelligent screening approaches. Future research priorities include DNA methylation-based markers, circulating microRNA signatures, and artificial intelligence-assisted diagnostic platforms to improve early detection accuracy and complement LDCT screening.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arecoline-induced EV-mediated ZNF582 hypermethylation drives IFIT1-PD-L1 immune evasion in oral squamous cell carcinoma.","authors":"Hui-Hsin Ko, Hsin-Hui Peng, Chun-Pin Chiang, Hsiang-Fong Kao, Hung-Ying Lin, Mark Yen-Ping Kuo, Shih-Jung Cheng","doi":"10.1186/s13148-026-02066-4","DOIUrl":"10.1186/s13148-026-02066-4","url":null,"abstract":"<p><strong>Background: </strong>This study examined the role of arecoline-induced zinc finger protein 582 (ZNF582) methylation via extracellular vesicles (EVs) in oral squamous cell carcinoma (OSCC) and its effect on PD-L1 expression through the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) pathway.</p><p><strong>Materials and methods: </strong>EVs were isolated from SAS and TW2.6 cancer cell lines using ultracentrifugation and characterized using electron microscopy. ZNF582 methylation and protein expression were assessed, with stemness and epithelial-mesenchymal transition (EMT) markers analyzed via Western blotting. T cell populations were evaluated using flow cytometry.</p><p><strong>Results: </strong>Arecoline-induced ZNF582 methylation via EVs reduced protein expression. ZNF582 knockdown promoted OSCC proliferation, migration, stemness, and EMT, and increased PD-L1 expression, aiding immune evasion via IFIT1. PD-L1 expression was linked to lower CD4+/CD8 + T cell ratios in OSCC patients.</p><p><strong>Conclusion: </strong>Arecoline-induced ZNF582 hypermethylation via EVs promotes immune evasion through IFIT1, suggesting a potential therapeutic target for OSCC treatment.</p><p><strong>Clinical relevance: </strong>Targeting the EV-mediated ZNF582-IFIT1-PD-L1 pathway may offer new therapeutic strategies for immune modulation in OSCC patients, especially those with a history of areca nut exposure.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation profiling in Huntington's disease reveals disease associated changes in the striatum.","authors":"Gregory Wheildon, Adam R Smith, Luke Weymouth, Joshua Harvey, Morteza Kouhsar, Lachlan F MacBean, Claire Troakes, Ehsan Pishva, Rebecca G Smith, Katie Lunnon","doi":"10.1186/s13148-026-02082-4","DOIUrl":"10.1186/s13148-026-02082-4","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease is caused by a trinucleotide CAG repeat expansion in the HTT gene. Despite displaying autosomal dominance, phenotypic variation exists amongst mutation carriers, in particular relating to the age that symptoms first occur. This variation is primarily driven by an inverse relationship between CAG expansion size and age of symptom onset. However, the majority of variation in age of onset that is independent of CAG repeat length is thought to be driven by environmental influences. Since DNA methylation can be altered by environmental factors, and as methylomic variation is reported in other neurodegenerative diseases, it may offer a potential mechanism underlying disease manifestation.</p><p><strong>Results: </strong>We utilized the Illumina EPIC v1 methylation array to profile DNA methylation in 120 samples, including three distinct brain regions (striatum, entorhinal cortex and cerebellum) in 20 Huntington's disease and 22 control donors. We identified seven Bonferroni-significant differentially methylated CpGs within the striatum along with 27 differentially methylated regions, annotated to genes involved in physiological processes known to be disrupted in HD such as the urea cycle and metabolism. Weighted gene correlation network analysis identified modules of co-methylated CpGs that were associated with Huntington's disease, with ontological analyses showing enrichment in disease relevant processes. Furthermore, integration of single-nuclei RNA sequencing data highlighted that genes annotated to these modules are enriched in striatal spiny projection neurons, the primary cell types affected in the disease.</p><p><strong>Conclusions: </strong>Here, we present the first epigenome-wide association study of Huntington's disease conducted in the striatum, the primary region of neuropathology, along with matched entorhinal cortex and cerebellum on the Illumina EPIC v1 array. Our results suggest that DNA methylation is altered at loci associated with Huntington's disease in disease relevant regions and cell types and strengthens evidence for areas of potential therapeutic intervention.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13202909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA demethylation of ANXA4 is associated with atrial fibrillation risk through myeloid immune mechanisms: evidence from Mendelian randomization and multi-omics analyses.","authors":"Qingyi Zeng, Jingjing Xiang, Yilan Li, Mengjun Huang, Zhanglan Wang, Mengjiang Hu, Weihong Sun, Haiwen Li, Tao Xu, Nian Den, Zhengmei Zhou, Jin Chen, Jingjing Chen, Wei Li","doi":"10.1186/s13148-026-02131-y","DOIUrl":"10.1186/s13148-026-02131-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Atrial fibrillation (AF) is a common arrhythmia affecting millions of patients globally. While epigenetic modifications play a significant role in cardiovascular diseases, their contribution to AF remains incompletely understood. Annexin A4 (ANXA4), a calcium-dependent phospholipid-binding protein, is implicated in inflammation and immune-mediated diseases, but its epigenetic regulation and mechanistic role in AF pathogenesis have not been systematically explored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study employed a multi-omics approach, integrating Mendelian randomization (MR), DNA methylation quantitative trait loci (mQTL)-mediated analysis, bulk and single-cell transcriptomics, and clinical validation. Two-sample MR utilized plasma proteome quantitative trait loci data from 4759 Icelandic individuals and AF genome-wide association study summary statistics from FinnGen and OpenGWAS databases. mQTL-based mediation analysis leveraged data from 27,750 individuals, and ANXA4 promoter methylation in atrial tissue was assessed in the GSE62727 dataset. Clinical validation involved qPCR for ANXA4 mRNA and CpG sites cg11942603 and cg22792910 in peripheral blood from 130 participants (77 AF patients and 53 sinus rhythm controls). Additionally, ANXA4 protein levels in peripheral blood leukocytes were analyzed using Western Blotting. Machine learning models were used to assess diagnostic performance, and logistic regression analyzed clinical associations.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;MR analysis provided evidence consistent with genetically predicted higher ANXA4 levels increasing AF risk (odds ratio = 1.17, 95% CI 1.11-1.23, P = 1.73 × 10&lt;sup&gt;-10&lt;/sup&gt;), with Bayesian colocalization supporting a shared genetic signal at rs17037076. mQTL-based mediation analysis indicated that hypomethylation at cg11942603 and cg22792910 significantly mediated the association between ANXA4 and AF. Peripheral blood and atrial tissue analyses confirmed lower methylation levels at cg11942603 in AF patients. qPCR confirmed significantly elevated ANXA4 mRNA expression in the peripheral blood of AF patients. Western Blot analysis further revealed a significant increase in intracellular ANXA4 protein levels within peripheral blood leukocytes of AF patients (P = 0.01). Single-cell RNA sequencing showed higher ANXA4 expression across various immune cell types in AF. Larger left atrial diameter, log-transformed NT-proBNP, and ANXA4 mRNA were independently associated with AF, while higher ANXA4 methylation was associated with lower odds of AF. Machine learning models demonstrated high discriminative ability for AF diagnosis (AUC 0.949-0.962).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our multi-omics approach provides evidence that hypomethylation at specific ANXA4 CpG sites is associated with increased gene expression and elevated AF risk. Increased ANXA4 mRNA and protein levels are associated with an enhanced immune response, particularly in myeloid cel","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}