Clinical Epigenetics最新文献

{"title":"Epigenome-wide DNA methylation and spontaneous preterm birth among pregnant black women.","authors":"Tingting Zhao, Yihong Zhao, Paolo Reho, Goleen Samari, Ronald Wapner, Arielle Hazi, Haotian Wu, Veronica Barcelona","doi":"10.1186/s13148-026-02151-8","DOIUrl":"10.1186/s13148-026-02151-8","url":null,"abstract":"<p><strong>Background: </strong>Preterm birth (PTB, < 37 weeks of gestation) is a major public health concern in the United States, with Black women experiencing a higher incidence compared to White women. Although some studies have identified social, medical, and obstetric risk factors for PTB, the biological mechanisms underlying spontaneous PTB (sPTB) risk remain unclear. We conducted a secondary analysis using data from Black participants enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b), (n = 1073) from 2010 to 2013. Peripheral whole blood samples were collected from all participants between 6 + 0/7 and 13 + 6/7 weeks of gestation. Demographic, behavioral and clinical data were gathered through surveys, and pregnancy outcomes were obtained through chart abstraction. We used the Infinium Methylation EPIC v2.0 BeadChip for epigenome-wide association (EWAS) of DNA methylation and sPTB.</p><p><strong>Results: </strong>We identified 19 differentially methylated CpGs associated with sPTB, 17 CpGs were mapped to 27 annotated genes including CASR (cg19108881), KLF2/ KLF2-DT (cg18473733), SNX14/SYNCRIP (cg25689730), FBXO2 (cg04872402), HPAT5/LOC102725048 (cg12798411), RTN4RL1/LOC105371486 (cg03098704), SETD4 (cg25826287), SLC25A16 (cg15165108), CLYBL/CLYBL-AS3 (cg12328625), HES7 (cg09601704), SLC67A1/ SLC67A1-AS (cg05919744), ATP2A3 (cg12120292), PSMB8/PSMB8-AS1/ PSMB9, TAP2 (cg24031377), SLCO3A1 (cg05111081), KIAA1671 (cg26144263), ALDH4A1 (cg 12,092,708), and GUCD1 and SNRPD3 (cg11895717). Functional enrichment analysis revealed molecular functions related to enzymatic protein degradation (threonine peptidases) and energy-dependent transport of substances across membranes and biological processes including cellular transport and vascular regulation, which may influence early embryonic development and contribute to sPTB risk.</p><p><strong>Conclusions: </strong>Our study identified potential epigenetic alterations associated with sPTB risk and highlighted candidate genes, molecular functions, and biological processes that may serve as predictors in pregnant Black women. Future research should examine larger samples of Black women and include social determinants of health (SDOH) such as individual- and structural- racism to explain racial disparities in methylation patterns. There is a need for larger studies that examine the interactions between SDOH and epigenomic mechanisms underlying adverse birth outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13377820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148013724","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":"Early detection of gastric cancer with the assistance of cell-free DNA fragmentomics.","authors":"Xiaoli Huang, Zhengxiang Han, Ying Zhang, Hongmei Wang, Xuqi Li, Chenxi Bai, Ying Pan, Jingwen Huang, Jiaojiao Xie, Xiaohan Qian, Xuan Wang, Tao Ding, Jinpeng Zhang, Shanshan Yang, Xinyue Hong, Qifan Jing, Gang Li, Xiaohua Li","doi":"10.1186/s13148-026-02150-9","DOIUrl":"10.1186/s13148-026-02150-9","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer remains one of the most prevalent malignancies globally. As early-stage gastric cancer is typically asymptomatic or presents with non-specific symptoms, most patients are diagnosed at advanced stages, leading to poor survival outcomes. Effective early detection strategies are important for reducing gastric cancer-related mortality. In this study, we developed a non-invasive assay utilizing cell-free DNA to distinguish patients with early-stage gastric cancer from healthy individuals.</p><p><strong>Results: </strong>We performed low-depth whole genome sequencing to profile cell-free DNA and extracted three distinct features: fragment size patterns, coverage at transcription factor binding sites, and methylation-based profiles. These features were integrated via machine learning to construct a stacked ensemble model. The study included a training cohort (108 gastric cancer patients and 108 healthy controls), a temporally independent validation cohort (79 patients and 79 healthy controls), and an external validation cohort recruited from two independent centers (136 patients and 136 healthy controls). The ensemble model demonstrated robust performance, achieving area under the curve values of 0.986, 0.978, and 0.967 in the training, validation, and external cohorts, respectively. Specificity and sensitivity were 98.1% and 89.8% in the training cohort, 97.5% and 87.6% in the validation cohort, and 96.3% and 87.5% in the external cohort. Notably, the sensitivity for detecting stage I gastric cancer exceeded 85% across all cohorts.</p><p><strong>Conclusions: </strong>By integrating multi-dimensional cell-free DNA fragmentomic features, this assay provides accurate, non-invasive detection of gastric cancer, particularly at early stages. While its performance was high, the specificity reported here may be overestimated due to the use of a strictly screened healthy control group. Nevertheless, this fragmentomic-based approach represents a promising tool to complement existing screening strategies, potentially improving early diagnosis rates.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148005052","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":"Accelerated biological aging and underlying epigenetic modification mediated the association between obesity and asthma.","authors":"Jian Liu, Zhengqi Song, Chengge Shi, Xinan Lu, Aijun Zhang, Yihe Chen, Xuejia Zhang","doi":"10.1186/s13148-026-02145-6","DOIUrl":"10.1186/s13148-026-02145-6","url":null,"abstract":"<p><strong>Background: </strong>The relationships among obesity, accelerated biological aging, and asthma, as well as the underlying epigenetic mechanisms, remain incompletely understood.</p><p><strong>Methods: </strong>We conducted a prospective cohort study in the UK Biobank to evaluate whether accelerated biological aging mediates the association between obesity and incident asthma. We then performed two-sample Mendelian randomization (MR) to assess the potential causal effect of accelerated biological aging on asthma from an epigenetic perspective. Epigenetic MR and colocalization analyses were used to prioritize aging-related DNA methylation (DNAm) CpG sites associated with asthma. Finally, single-cell RNA sequencing (scRNA-seq) was applied to characterize the cell-type-specific expression patterns of CpG-mapped genes.</p><p><strong>Results: </strong>In the UK Biobank cohort, KDM-BA acceleration and PhenoAge acceleration partially mediated the association between obesity and asthma, with proportions mediated of 4.0% and 12.2%, respectively. Two-sample MR further suggested that DNAm PhenoAge acceleration was associated with a higher risk of asthma (OR = 1.02; 95% CI: 1.01-1.03; P = 0.004). Epigenetic MR and colocalization analyses suggested that cg02010481 (JAZF1), cg17929770 (RSPH6A), cg19927816 (SYMPK; RSPH6A), cg08544331 (RUNX3), cg15498134 (RUNX3), and cg04389704 (FBXL19) were associated with a reduced risk of asthma, whereas cg16553500 (COL16A1), cg16351569, cg10036013 (FOXK1), cg11647481 (FOXK1), cg23776012 (KRT222), and cg08258403 were associated with an increased risk of asthma. In scRNA-seq analyses, JAZF1, SYMPK, FOXK1, and RUNX3 were differentially expressed across multiple immune cell types.</p><p><strong>Conclusions: </strong>This study demonstrates that accelerated biological aging partially mediates the association of obesity with asthma and further elucidates underlying epigenetic mechanisms linking aging to asthma.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986859","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":"Methylation-based biomarkers from thin-prep cytology test samples for early detection of cervical cancer: application and clinical potential.","authors":"Zhihan Liu, Guorong Liu, Shuanping Liu, Xiuxiu Wang, Yunshi Liang, Yuanyuan Guo, Baochen Du, Nabo Miao, Wenli Shi, Qiuyun Zhu, Liping Yu, Cui Deng, Guo Chen, Lijuan Huang, Lingling Zhan, Xiangyu Zheng, Jie Zhao, Yongjun Li, Xiaoliang Han, Yang Cheng, Jing Yang","doi":"10.1186/s13148-026-02154-5","DOIUrl":"10.1186/s13148-026-02154-5","url":null,"abstract":"<p><strong>Background: </strong>Although human papillomavirus (HPV) testing and Thin-Prep Cytology Test (TCT) are currently adopted as the first-line screening methods for cervical cancer, both of them have limitations. This study aimed to develop and validate new methylation-based biomarkers from formalin-fixed paraffin-embedded (FFPE) tissue and TCT samples in a Chinese population to improve early detection of cervical cancer (CC).</p><p><strong>Methods: </strong>We performed a differential methylation analysis of cervical FFPE tissues and TCT samples through targeted methylation sequencing. Quantitative methylation-specific PCR (qMSP) was performed on cervical tissues, TCT samples and cell lines to construct a diagnostic model containing three highly methylated sites, namely JAM3, VSTM2B and EPHA7. The clinical effectiveness was evaluated on overall 279 TCT multiple group samples, comprising 33 squamous cell carcinomas (SCC), 14 adenocarcinoma(ADC), 43 high-grade squamous intraepithelial lesion (HSIL), 49 low-grade squamous intraepithelial lesion (LSIL), 78 high risk-HPV (HR-HPV)-positive/cytology-normal (NILM) cases, 32 healthy controls (NC), and 30 benign gynecological samples. The model performance was assessed using sensitivity, specificity, and area under the receiver operating characteristic curve (AUC).</p><p><strong>Results: </strong>In an independent validation cohort (n = 108), the panel of three methylation-based biomarkers showed outstanding diagnostic accuracy. It achieved sensitivities of 100.0% for SCC (n = 10), 80.0% for ADC (n = 5), and 86.7% for HSIL (n = 15). Specificity was 90.6% in HR-HPV-positive women (n = 32), 100.0% in NC (n = 12), and 93.3% in other benign conditions (n = 15), with 89.5% specificity in LSIL (n = 19). Overall sensitivity and specificity were 90.0% and 92.3%, respectively. HPV subtype-stratified analysis revealed 90.9% sensitivity and 85.7% specificity for HPV16/18-positive samples, with consistent performance for non-HPV16/18 subtypes (85.7% sensitivity, 89.5% specificity).</p><p><strong>Conclusions: </strong>The JAM3/VSTM2B/EPHA7 methylation model (JAM3^m/VSTM2B^m/EPHA7^m) has shown excellent performance in the detection of cervical cancer and precancerous lesions. It provides a new direction for overcoming the limitations of the traditional HPV and TCT combined screening method.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986899","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":"Histone H3K27 demethylation drives Crohn's disease inflammation: GSK-J4 as a potential epigenetic therapy.","authors":"Jigisha A Patel, Kevin Beatson, Jeries Abu-Hanna, Rijan Gurung, Paul Harrow, Christopher Wood, Marilena Loizidou, Lucie H Clapp, C Richard Cohen, Mohammad Mahmoud Rajab Eddama","doi":"10.1186/s13148-026-02165-2","DOIUrl":"10.1186/s13148-026-02165-2","url":null,"abstract":"<p><strong>Background: </strong>Crohn's disease (CD) is characterised by recurrent gastrointestinal inflammation. Epigenetic modifications, particularly the methylation of histone H3 at lysine 27 trimethylation (H3K27me3), are crucial in regulating gene expression and macrophage activity. Dysregulation of these modifications may contribute to CD pathogenesis.</p><p><strong>Objective: </strong>To investigate the role of H3K27me3 in CD, assess the involvement of the WNK1-TAK1 signalling pathway, and evaluate the therapeutic potential of GSK-J4, a selective histone demethylase inhibitor.</p><p><strong>Methods: </strong>Peripheral blood and intestinal tissue were collected from CD patients (n = 19) undergoing surgical resection and from age-matched healthy controls (HC, n = 17). Monocytes were isolated and differentiated into macrophages. Expression of H3K27me3, demethylases KDM6A and KDM6B, and components of the WNK1-TAK1 pathway were assessed by Immunofluorescence, Western blotting, and qRT-PCR. GSK-J4 was used to assess its effect on these markers and cytokine secretion.</p><p><strong>Results: </strong>Inflamed CD tissue and derived macrophages showed increased KDM6A/B expression and reduced H3K27me3 compared with unaffected tissue and HC-derived macrophages. GSK-J4 treatment reversed this epigenetic profile and significantly reduced secretion of inflammatory cytokines IL-6, IL-10, and TNF-α. Activation of the WNK1-TAK1 axis was identified as a key mediator of lipopolysaccharide-induced cytokine release and was modulated by GSK-J4.</p><p><strong>Conclusion: </strong>This study identifies KDM6A/B-driven epigenetic dysregulation as a novel pathogenetic mechanism in CD. GSK-J4 effectively restores H3K27me3 levels and reduces inflammation, supporting histone demethylase inhibition as a promising and mechanistically novel therapeutic approach warranting further translational investigation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986886","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":"Fluid shear stress enhances pancreatic cancer motility through YAP activation.","authors":"Juan Deng, Giulia Lencioni, Aldo Pastore, Adam E Frampton, Dongmei Deng, Elisa Giovannetti","doi":"10.1186/s13148-026-02163-4","DOIUrl":"10.1186/s13148-026-02163-4","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate due to late-stage diagnosis. Although SUIT2 sublines differ in metastatic and drug-resistant behavior, the mechanisms behind these differences are unclear. Fluid shear stress can regulate tumor cell migration, and the mechanosensitive factor yes-associated protein (YAP) promotes PDAC progression. However, the impact of shear stress on YAP signaling in PDAC cells remains unknown. This study aims to better understand how fluid shear stress influences the behavior of PDAC cells and to elucidate the mechanisms by which shear stress regulates their metastatic potential, in order to support the development of more effective therapeutic strategies.</p><p><strong>Results: </strong>Using the BioFlux-Shear-Flow-System, we observed that under static conditions, the more metastatic SUIT2-007 cells displayed greater migratory capacity than the less metastatic SUIT2-028 cells. However, exposure to fluid shear stress significantly enhanced the migration capacity of SUIT2-028 cells. Consequently, the migratory capacities of the two cell lines became comparable under shear stress conditions. RNA-sequencing revealed differences in yes-associated protein (YAP) activation between SUIT2-028 and SUIT2-007. Functional assays using a YAP activation inhibitor and scratch assay demonstrated that inhibition of YAP activity reduced migration in both tumor cell lines and abolished the differences in their migratory capacities.</p><p><strong>Conclusions: </strong>Our findings highlight YAP as a mechanosensitive regulator of pancreatic cancer cell migration under shear stress, offering insights into how biomechanical forces can drive metastatic capacity.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980795","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":"APOL1 risk genotypes influence DNA methylation across multiple genomic elements in APOL1-APOL4- MYH9 region in African Americans.","authors":"Yang Li, Anne K Bozack, Pascal Schlosser, Eugene P Rhee, Aditya Surapaneni, Alex Waterhölter, Zulema Rodriguez-Hernandez, Kelly V Ruggles, Josef Coresh, Morgan E Grams","doi":"10.1186/s13148-026-02147-4","DOIUrl":"10.1186/s13148-026-02147-4","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic modification of the APOL1 gene carrying risk alleles (G1 and G2) may represent a therapeutic strategy for APOL1-related kidney diseases. However, DNA methylation changes associated with APOL1 have not been thoroughly characterized.</p><p><strong>Methods: </strong>We conducted an epigenome-wide association study (EWAS) of APOL1 risk alleles in 399 African Americans with chronic kidney disease (CKD) from the Atherosclerosis Risk in Communities (ARIC) study cohort using blood DNA samples. These associations were further examined in 1,677 African Americans with preserved kidney function. Additionally, the relationships between the identified CpGs and the expression of APOL1 and nearby genes were evaluated in normal kidney tissue. APOL1 risk-associated CpGs were tested for associations with estimated glomerular filtration rate based on creatinine and cystatin C (eGFR_crcys) and with urine albumin-to-creatinine ratio (ACR). Methylation patterns were additionally assessed for differentially methylated regions and associations with kidney function. We further evaluated whether APOL1 risk-associated CpGs can modulate the relationship between APOL1 risk alleles and kidney function measures.</p><p><strong>Results: </strong>Four CpGs (cg15716373, cg16528833, cg21032535, and cg14589586) were significantly associated with APOL1 risk alleles, mapping to two enhancers and two promoters within the APOL1-APOL4-MYH9 region. Among APOL1 high-risk carriers, cg14589586 in the APOL2 promoter was inversely correlated with cg15716373 in an APOL1 intron, a pattern absent in White Americans. The association between the four CpGs and APOL1 risk alleles was also present among participants with preserved kidney function. In normal kidney tissue, cg14589586 and cg16528833 were significantly associated with the expression levels of multiple genes in this region, including APOL1 and MYH9. Multiple CpGs located within the APOL1-APOL4-MYH9 region exhibited significant joint associations with eGFR_crcys and ACR. APOL1 risk-associated CpGs showed significant interactions with APOL1 risk alleles in relation to kidney function.</p><p><strong>Conclusion: </strong>APOL1 risk alleles are associated with complex DNA methylation alterations across the APOL1-APOL4-MYH9 region, potentially regulating multiple genes within this locus. APOL1 risk-associated CpGs may represent therapeutic targets for APOL1-related kidney diseases.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980776","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":"NSD1 governs H3K36me2-mediated DNA methylation and drives endo-mesodermal differentiation of human iPSCs.","authors":"Anna Hansknecht, Martina Mankarious, Monica Varona Baranda, Esra Dursun Torlak, Wolfgang Wagner, Kira Zeevaert, Deepika Puri","doi":"10.1186/s13148-026-02162-5","DOIUrl":"10.1186/s13148-026-02162-5","url":null,"abstract":"<p><p>Epigenetic regulatory mechanisms, which include histone modifications and DNA methylation, play a central role in development and aging. Dimethylation of H3K36, deposited mainly by the histone methyltransferase NSD1, occurs predominantly in intergenic regions, and recruits the DNA methyltransferase DNMT3A to facilitate DNA methylation. Haploinsufficiency of NSD1 results in the overgrowth disorder Sotos syndrome in vivo, which is associated with aberrant DNA methylation signatures and an enhanced epigenetic age. To understand the mechanisms by which NSD1 may regulate development, differentiation, and diseases, we generated human iPSC lines deficient in functional NSD1 (NSD1-KO). NSD1-KO cells exhibit a substrate-specific decrease in proliferation, reduced H3K36me2 levels, and extensive DNA hypomethylation. Notably, the loss of functional NSD1 altered the differentiation potential of iPSCs, with aberrant endodermal and mesodermal lineage commitment. Further analysis revealed that NSD1 might drive endodermal differentiation by regulating the expression of an endodermal lncRNA 'HIDEN' by mechanisms independent of the regulation of DNA methylation. Our NSD1-KO iPSC lines partially recapitulate the DNA methylation defects associated with NSD1-related developmental disorders. Additionally, we uncovered a novel mechanism by which NSD1 may regulate endodermal differentiation of human iPSCs.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971003","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":"Association between pace of aging estimated from blood DNA methylation and all-cause mortality: the HUNT study.","authors":"Yi-Qian Sun, Ilona Urbarova, Lin Jiang, Therese Haugdahl Nøst, Xiao-Mei Mai","doi":"10.1186/s13148-026-02070-8","DOIUrl":"10.1186/s13148-026-02070-8","url":null,"abstract":"<p><strong>Background: </strong>Epigenetic clocks, developed using blood DNA methylation data, can be used to estimate biological ages and pace of aging. We aimed to identify potential determinants of the pace of aging, estimated using blood DNA methylation, and to investigate the association between the pace of aging and all-cause mortality in a population-based Norwegian cohort with repeated DNA methylation measurements.</p><p><strong>Methods: </strong>This study included 140 cancer-free controls from a lung cancer nested case-control study within the Trøndelag Health Study (HUNT). DNA methylation was measured in blood samples in both HUNT2 (1995-97) and HUNT3 (2006-08), 11 years apart. The pace of aging was estimated using two established measures of biological age, DNAmPhenoAge and DNAmGrimAge2, and two direct measures of pace of aging, DunedinPoAm and DunedinPACE, all derived from blood DNA methylation data. All-cause mortality was followed up until 2023.</p><p><strong>Results: </strong>There was a moderate to excellent reliability of the repeated measurements, with intraclass correlation coefficient (ICC) values ranged from 0.69-0.91. University education appeared to be associated with a slower pace of aging, while smoking and obesity were associated with a faster pace. A one-standard deviation increase in the pace of aging, as measured by DNAmGrimAge2, was associated with a hazard ratio (HR) of 2.42 (95% confidence interval (CI) 1.25 to 4.68) for all-cause mortality in HUNT2, and a HR of 2.30 (95% CI 1.22 to 4.33) in HUNT3 after adjustment for the established risk factors.</p><p><strong>Conclusions: </strong>The pace of aging, as estimated using blood DNA methylation, appears to be an independent predictor of all-cause mortality. This measure may reflect the combined influence of genetic, lifestyle, and environmental factors on individual aging trajectories.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980826","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":"Concordant epigenetic and discordant clinical PHP1B/iPPSD3 manifestations in two monozygotic adolescent twins.","authors":"Gustavo Perez-Nanclares, Africa Manero-Azua, Gema Grau, Arrate Pereda, June Corcuera, Esther Navarro, Ainhoa Camille Aranaga-Decori, Alejandro García-Castaño, Belén de la Morena-Barrio, Luis Castano, Guiomar Perez de Nanclares","doi":"10.1186/s13148-026-02160-7","DOIUrl":"10.1186/s13148-026-02160-7","url":null,"abstract":"<p><strong>Background: </strong>Imprinting disorders are caused by epigenetic alterations leading to abnormal gene expression from imprinted loci. Pseudohypoparathyroidism type 1B is characterized by methylation defects at the GNAS locus, affecting hormone responsiveness. Monozygotic twins discordant for imprinting disorders provide a unique opportunity to investigate the timing, maintenance, and tissue-specific distribution of epimutations and their relation to clinical expression. Most previous studies focus on infants, where fetal blood chimerism may influence epigenetic profiles, but data in adolescents remain scarce.</p><p><strong>Results: </strong>We studied adolescent monozygotic twin sisters presenting clinical and biochemical discordance for pseudohypoparathyroidism type 1B. Both twins exhibited an identical, partial methylation defect at the GNAS locus in peripheral blood, consistent with a postzygotic epigenetic alteration occurring before embryonic splitting. Exclusion of known genetic causes, including uniparental disomy and structural variants, and absence of multilocus imprinting disturbances or maternal-effect gene mutations, were confirmed through comprehensive genomic and methylation analyses. The affected twin showed involvement of methylation abnormalities across all three germ layers derived tissues, whereas the unaffected twin presented very mild or absent defects in some tissues, possibly explaining the phenotypic divergence. The persistent concordance of partial methylation defects in blood despite phenotypic discordance suggests stable early epimutations maintained in hematopoietic progenitors, while tissue-specific mosaicism and differential methylation maintenance across organs critical to disease expression contribute to clinical differences. Advanced long-read sequencing demonstrated sensitivity for detecting partial and mosaic methylation patterns, rather than just complete alterations.</p><p><strong>Conclusions: </strong>This study underscores the complexity of epigenetic mosaicism in imprinting disorders, highlighting that early postzygotic partial epimutations may yield identical blood methylation profiles but divergent tissue distributions, leading to discordant clinical phenotypes in monozygotic twins. The adolescent age of our subjects challenges the fetal blood chimerism explanation for methylation concordance and emphasizes the importance of multi-tissue evaluation and sensitive molecular assays. These findings have important implications for diagnosis, monitoring, and genetic counseling in imprinting disorders, advocating for integrated approaches to assess epigenetic heterogeneity and phenotypic variability.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147971052","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}