Clinical Epigenetics最新文献

{"title":"CCR1 as a potential regulator of neutrophil-mediated pathogenesis in post-acute ischemic stroke: a multi-omics Mendelian randomization.","authors":"Xiaoguang Zhang, Xuerui Xiang, Ruoyu Li, Jiehong Huang, Yi Yang, Hongkai Yao, Xining Ren, Liang Hu, Yunping Song, Lingjing Jin","doi":"10.1186/s13148-026-02132-x","DOIUrl":"https://doi.org/10.1186/s13148-026-02132-x","url":null,"abstract":"<p><strong>Background: </strong>The genetic and immunological mechanisms underlying post-acute ischemic stroke (IS) remain incompletely understood, particularly those involving neutrophil-mediated inflammation. This study aimed to identify genes associated with IS using a multi-omics Mendelian randomization framework.</p><p><strong>Methods: </strong>Summary-data-based Mendelian Randomization (SMR) was used to identify upstream genetic regulators of neutrophil-driven pathogenesis. We systematically screened 949 neutrophil-related genes using SMR analyses across multi-omics quantitative trait loci (QTL) datasets (methylation, expression, and protein). We then validated temporal expression patterns in independent IS cohorts and constructed a diagnostic nomogram to assess clinical discrimination.</p><p><strong>Results: </strong>Multi-omics SMR analysis identified CCR1, DEFA4, SH2B3 and CDKN1A as potential genes associated with IS risk. In independent clinical validation cohorts, CCR1 and DEFA4 were consistently upregulated in the peripheral blood of IS patients. Notably, CCR1 emerged as a central hub gene; its expression exhibited a potential association with neutrophil abundance (R = 0.31) and functional hyperactivation pathways, including chemotaxis and cytotoxicity. Furthermore, a diagnostic nomogram integrating CCR1 and DEFA4 demonstrated high discriminatory power (AUC = 0.875), underscoring their potential as precision biomarkers.</p><p><strong>Conclusions: </strong>Identified as a potential neutrophil-related genetic factor, CCR1 is associated with ischemic injury and may contribute to neutrophil chemotaxis and functional hyperactivation. Consequently, targeting CCR1 offers a precision therapeutic strategy to attenuate neuroinflammation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.","authors":"Janina Müller, Emre Sofyali, Luisa Schwarzmüller, Yael Aylon, Eviatar Weizman, Lisa Schlicker, Katherine Kelly, Simone Borgoni, Simin Oz, Cole Stocker, Sara Burmester, Angelika Wörner, Sabine Karolus, Birgitta E Michels, Daniela Heiss, Rainer Will, Veronica Rodrigues de Melo Costa, Pavlo Lutsik, Dieter Weichenhan, Ilse Hofmann, Nishanth Belugali Nataraj, Yosef Yarden, Luca Magnani, Christoph Plass, Almut Schulze, Cindy Körner, Moshe Oren, Stefan Wiemann","doi":"10.1186/s13148-026-02133-w","DOIUrl":"10.1186/s13148-026-02133-w","url":null,"abstract":"<p><strong>Background: </strong>Estrogen receptor alpha (ERα)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success.</p><p><strong>Results: </strong>We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling, however, independently of estrogen.</p><p><strong>Conclusions: </strong>These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764519","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":"Lactylation and targeted therapy resistance in hepatocellular carcinoma.","authors":"Siying Zhu, Chuchu Tan, Qin Tan, Wenliang Tan, Yingzheng Tan","doi":"10.1186/s13148-026-02139-4","DOIUrl":"https://doi.org/10.1186/s13148-026-02139-4","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) persists as a leading cause of cancer-related mortality globally. While targeted therapies, including sorafenib and lenvatinib, serve as standard first-line treatments, their efficacy is frequently compromised by low response rates and the rapid development of resistance, posing a significant clinical challenge. Lactylation (Kla), a metabolism-driven post-translational modification stemming from lactate accumulation, has recently emerged as a pivotal regulator of HCC progression and therapeutic resistance. The extent of lactylation is governed by lactate availability, the dynamic balance between \"writer\" and \"eraser\" enzymes, and chromatin accessibility. Functionally, Kla augments HCC malignancy by stimulating cell proliferation, modulating metabolic enzyme activity, promoting angiogenesis, and facilitating the remodeling of an immunosuppressive microenvironment. Mechanistically, it confers resistance to targeted therapy by activating antioxidant pathways, sustaining cancer stemness, and reinforcing metabolic reprogramming. Promising strategies to counteract this resistance involve inhibiting lactate production, targeting lactylation \"writers,\" and combining targeted agents with glycolysis inhibitors. This review delineates the regulatory network of lactylation, and the mechanisms of Kla-mediated drug resistance, as well as discusses potential therapeutic strategies to improve patient outcomes. Targeting the lactylation pathway thus represents a promising approach to reverse resistance and enhance the efficacy of targeted therapy in HCC.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of multilocus imprinting disturbance (MLID) in 101 Beckwith-Wiedemann spectrum patients.","authors":"Mario Cazalla, Alejandro Parra, Carlos Rodríguez-Antolín, Cristina Silván, Lucía Miranda-Alcaraz, Mónica Mora-Gómez, Natalia Gallego-Zazo, Manuel Rodríguez-Canó, Juan A Jiménez-Estrada, Pedro Arias, Enrique Galán Gomez, Antonio González-Meneses, Pablo Barbero, Vanesa Lotersztein, Mathis Hildonen, Zeynep Tümer, Alfredo Santana, Feliciano Ramos, Víctor L Ruiz-Perez, Jair Tenorio-Castano, Julián Nevado, David Monk, Pablo Lapunzina","doi":"10.1186/s13148-026-02077-1","DOIUrl":"https://doi.org/10.1186/s13148-026-02077-1","url":null,"abstract":"<p><p>Beckwith-Wiedemann spectrum (BWSp) is an overgrowth disorder caused by both genetic and epigenetic defects within the 11p15.5 chromosomal region. The most common cause of BWSp is DNA methylation anomalies in two imprinting control regions (ICR1, the telomeric centre that includes H19/IGF2:IG-DMR and ICR2, the centromeric centre that includes KCNQ1OT1:TSS-DMR) located within the 11p15.5 locus. Previous studies demonstrated that a subset of BWSp patients had methylation defects extending beyond 11p15.5 to other chromosomal loci, an entity known as multilocus imprinting disturbances (MLID). In this study, the multilocus methylation status of 101 BWSp patients was analysed by both various methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA-E034) and methylation microarrays. MS-MLPA-ME034 detected MLID in 16 (15.8%) of the patients, which increased to 59 (58.4%) using methylation microarrays. ICR2 hypomethylation was observed in all MLID cases, and 28 imprinted differentially methylated regions (DMRs) were additionally detected. Recurrent loci associated with the genes such as GNAS, MEST, and DIRAS3, previously reported in MLID patients, were also observed as hypomethylated in our cohort. Seven out of the 48 (14.6%) MLID-BWSp patients with complete data on type of conception were born following assisted reproductive technologies (ART), indicating an appreciable proportion of MLID among ART-conceived pregnancies. This study underscores the value of genome-wide methylation analyses in revealing molecular complexity, improving diagnostic accuracy, and informing prenatal care in BWSp with MLID. Future research should further explore the long-term clinical implications of MLID and the underlying molecular mechanisms.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A liquid biopsy-based multi-methylation marker panel for minimally invasive gastric cancer screening.","authors":"Fengying Long, Yi Xu, Kang Wu, Xiaoyu Fu, Tangjie Gao, Shiya Luo, Lizhong Dai, Xiao-Ping Chen","doi":"10.1186/s13148-026-02143-8","DOIUrl":"https://doi.org/10.1186/s13148-026-02143-8","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is the fifth most prevalent cancer and the fifth leading cause of cancer-related mortality worldwide. The current gold standard for clinical diagnosis is gastroscopy, which, despite its high sensitivity and specificity, is limited by its invasive nature and high cost, making it unsuitable for large-scale screening. Furthermore, the diagnostic process lacks biomarkers that offer both high sensitivity and specificity. A screening model incorporating five methylation-based biomarkers (ELMO1, FGF12, NPY, SEPTIN9, ZNF671) was developed. Using these methylation profiles, GC risk prediction models were constructed employing Random Forest.</p><p><strong>Results: </strong>In the training cohort of 605 subjects (259 patients with gastric cancer, 346 controls), the model demonstrated an area under the curve (AUC) of 0.9585, accuracy of 87.93%, sensitivity of 81.85%, and specificity of 92.49%. In an independent validation cohort of 152 subjects (73 patients with gastric cancer, 79 controls), the model achieved an AUC of 0.8868, accuracy of 81.58%, sensitivity of 82.19%, and specificity of 81.01%. The model showed strong screening capability across various pathological stages (0 + IA + IB, IIA + IIB, IIIA + IIIB + IIIC, IV), with AUCs of 0.8210, 0.9149, 0.9357, and 0.9383, respectively. Validation results were consistent with those from the training cohort, indicating significant potential for early-stage detection.</p><p><strong>Conclusions: </strong>This study establishes a minimally invasive, peripheral blood DNA methylation-based detection method for GC screening. The model demonstrates robustness, high sensitivity, and specificity, offering an effective strategy for population-level screening. The primary limitations of this study include the relatively small size of the validation cohort and a significant imbalance in TNM stage distribution. Additionally, there is a potential limitation in accurately discriminating gastric cancer risk within high-risk precancerous populations based solely on the current model. It is necessary to formulate a larger-scale prospective verification plan in the future.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation in the placenta and household socioeconomic status: the SPAH study.","authors":"Ella O Beraldo, Ann E Borders, Amy M Inkster, Linda M Ernst, Alexa A Freedman, Jungwon Kim, Lauren S Keenan-Devlin, Maria S Peñaherrera, Wendy P Robinson, Gregory E Miller","doi":"10.1186/s13148-026-02136-7","DOIUrl":"https://doi.org/10.1186/s13148-026-02136-7","url":null,"abstract":"<p><strong>Background: </strong>Disparities in socioeconomic status have been associated with adverse pregnancy outcomes, including preterm birth and fetal growth restriction. As the barrier between maternal exposures and the fetus, the placenta has been proposed to play a role in the mechanisms leading to poor health outcomes seen with socioeconomic disadvantage. We hypothesized that exposure to lower SES during pregnancy may lead to altered placental DNA methylation (DNAme) that is in turn associated with other pregnancy outcomes.</p><p><strong>Methods: </strong>Placental samples from the Stress, Pregnancy, and Health Study (SPAH) study (n = 493) were processed for DNAme analysis using the Illumina Infinium MethylationEPIC BeadChip array. Linear modelling was used to assess whether placental DNAme was associated with household-level indicators of Socioeconomic Position, Financial Resources, and/or Disadvantage. We additionally tested for associations with DNAme-derived epivariables of inferred cell composition and epigenetic age acceleration.</p><p><strong>Results: </strong>At FDR < 0.05 and |∆β|> 0.05, we observed only 2 CpGs associated with Socioeconomic Position after correcting for gestational age and ancestry; no CpGs were associated with Resources or Disadvantage. We also examined a less stringent |∆β|> 0.02 threshold (the lower limit of technical detection in this cohort) to ensure we were not missing small-effect SES associations. At this threshold there were 77 and 22 CpGs associated with Socioeconomic Position and Disadvantage, respectively, although closer inspection revealed that these changes were strongly associated with Hispanic ethnicity, and were likely explained by unaccounted for genetic variation in this cohort. In epivariable analyses, higher values of the Resources composite were associated with decreased cytotrophoblast:syncytiotrophoblast ratios in XY placentas only; this ratio is a novel metric that may reflect patterns of placental maturation and decreases over toward term in normative pregnancies. No SES metrics were associated with epigenetic age acceleration.</p><p><strong>Conclusions: </strong>In this diverse pregnancy cohort, we found little evidence that SES measures were associated with widespread alterations in placental DNAme. Importantly, DNAme-SES associations observed prior to adjustment for genetic ancestry were attenuated after ancestry-informed modeling, highlighting the potential for confounding in epigenetic studies of social exposures, particularly in heterogeneous cohorts. Our findings underscore the importance of carefully accounting for ancestry-related variation in DNAme studies, and will inform the design of future studies aimed at investigating the molecular correlates of socioeconomic disparities in pregnancy and early life, and the associated adverse birth and developmental outcomes.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation profiles at hospital admission are associated with subsequent severe COVID-19 outcomes.","authors":"Fei-Man Hsu, Harry Pickering, Steve E Bosinger, Walter Eckalbar, Holden T Maecker, Seunghee Kim-Schulze, Al Ozonoff, Joann Diray-Arce, Joanna M Schaenman, Elaine F Reed, Matteo Pellegrini","doi":"10.1186/s13148-026-02138-5","DOIUrl":"https://doi.org/10.1186/s13148-026-02138-5","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2 infection leads to a wide range of clinical manifestations ranging from asymptomatic to fatal cases. DNA methylation plays a crucial role in modulating host responses to viral infections; however, its potential for forecasting COVID-19 disease progression has not been fully explored.</p><p><strong>Results: </strong>We aimed to explore the connection between DNA methylation and COVID-19 phenotypic trajectories by examining a subset of the IMPACC cohort (n = 75), which includes longitudinal samples from hospitalized COVID-19 patients grouped into five disease trajectory groups (TGs) based on respiratory severity during the acute phase of infection. Our findings reveal that DNA methylation is associated with respiratory status, hospitalization duration, and immune cell composition, including T cell depletion and band neutrophil accumulation during acute infection. DNA methylation profiles at hospital admission differ among TGs and are associated with subsequent disease progression. Furthermore, DNA de-methylation of specific distal enhancers correlated with TG, and DNA methylation patterns generally normalize post-resolution. Comparative analyses revealed that DNA methylation changes are more strongly associated with TGs than transcriptome profiles across time.</p><p><strong>Conclusions: </strong>This study highlights the association between DNA methylation and COVID-19 phenotypic trajectories and identifies CpG loci that could serve as potential biomarkers for identifying patients at heightened risk of severe COVID.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association of epigenetic age acceleration with internal smoking dose, risk of lung cancer, and all-cause mortality in cigarette smokers: the Multiethnic Cohort study.","authors":"Tyler Liu, Lenora W M Loo, Brian Z Huang, Brandon Quon, Cherie Guillermo, Kimberly D Siegmund, Lynne R Wilkens, Alika K Maunakea, Stephen S Hecht, Sharon E Murphy, Daniel O Stram, Loïc Le Marchand, Alexandra M Binder, S Lani Park","doi":"10.1186/s13148-026-02137-6","DOIUrl":"https://doi.org/10.1186/s13148-026-02137-6","url":null,"abstract":"<p><strong>Background: </strong>Among cigarette smokers, higher internal smoking dose is associated with elevated lung cancer risk and mortality, independent of smoking pack-years. Some measures of epigenetic age acceleration (EAA) are associated with cigarette smoking status and exposure, as well as lung cancer risk and overall mortality. No study has examined the association between EAA measures and internal smoking dose (total nicotine equivalents (TNE; nmol/mL)), and their shared relationship with lung cancer incidence and mortality in a multiethnic population.</p><p><strong>Methods: </strong>From a subgroup of Multiethnic Cohort Study participants who smoked cigarettes at the time of biospecimen collection (n = 1969), six epigenetic clocks were computed using blood-based DNA methylation (DNAm) array data. EAA measures were computed by calculating the residuals that results from regressing an epigenetic clock on chronological age. The association of urinary TNE with EAA measures were assessed using linear regression models, adjusted for age, sex, body mass index (BMI; kg/m²), DNAm-based estimates of blood cell composition, population stratification, and self-reported pack-years of cigarette smoking. To evaluate the associations of EAA with incident lung cancer risk (n = 176 cases) and all-cause mortality (n = 780 deaths) (from 13 years of follow-up), Cox proportional hazard models, with age as the time metric, adjusted for decade of birth, sex, BMI, years of education, creatinine, DNAm-based estimates of blood cell composition, population stratification, self-reported pack-years, and urinary TNE, were used.</p><p><strong>Results: </strong>A standard deviation (SD) increase of log-TNE was statistically significantly associated with increased AgeAccelPheno (beta = 0.416, 95% Confidence Interval (CI)=0.134-0.698)), AgeAccelGrim (beta = 0.771, 95%CI=0.603-0.939), and DunedinPACE (beta = 0.015, 95%CI=0.010-0.020). A SD increase of AgeAccelGrim (Hazard Ratio (HR) = 1.40; 95% CI   1.16-1.71) and DunedinPACE (HR = 1.31; 95% CI  1.11-1.55) were associated with a risk of lung cancer, whereas a SD increase of AgeAccelDNAm-based telomere length was inversely associated with lung cancer risk (HR = 0.79; 95% CI  0.67-0.93). These findings were similar for the hazard of all-cause mortality.</p><p><strong>Conclusions: </strong>Our study suggests that circulating methylation-based biomarkers of biological aging may provide information on lung cancer risk and all-cause mortality beyond that of self-reported pack-years and a (short-term) biomarker of internal smoking dose. If replicated, our findings suggest that epigenetic clocks may inform higher risk groups for prevention strategies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The non-linear and linear effects of CYP2C19 metaboliser status on DNA methylation: a methylome-wide association study.","authors":"Chen Shen, Mark J Adams, Eleanor Davyson, Matthew H Iveson, Simon R Cox, Sarah E Harris, Andrew M McIntosh, Xueyi Shen","doi":"10.1186/s13148-026-02125-w","DOIUrl":"https://doi.org/10.1186/s13148-026-02125-w","url":null,"abstract":"<p><strong>Background: </strong>CYP2C19 metabolises many medications. Its enzymatic activity can be inferred from genetic variants within CYP2C19 that link to the efficacy of drug treatments and their side effects. It is, however, unclear if enzymatic activity is associated with local or widespread differences in DNA methylation. DNA methylation differences associated with CYP2C19 metabolising status may also reveal interacting genes and pathways that underlie CYP2C19 effects on drug response and health consequences. A discovery methylome-wide association study (MWAS) was conducted in the Generation Scotland (n = 18,396) to investigate the non-linear and linear effects of CYP2C19 metaboliser status on DNA methylation. A targeted replication analysis on significant CpG sites from the discovery MWAS was conducted in Lothian Birth Cohorts of 1921 and 1936 (n = 1238). Pathway enrichment analysis was conducted for significant cytosine-guanine dinucleotide (CpG) sites. We examined whether the associations between CYP2C19 metaboliser status and DNA methylation were independent of the use of drugs that are inducers, inhibitors, or substrates of the CYP2C19 enzyme through interaction analysis.</p><p><strong>Results: </strong>Forty-eight CpG sites were significantly associated with the quadratic term of CYP2C19 metaboliser status (P_Bonferroni<0.05). Nineteen CpG sites, annotated to genes involving drug metabolism, inflammation, lipid levels, and Type 2 diabetes, demonstrated non-linear associations with CYP2C19 metaboliser status. Among the significant CpG sites in the discovery sample, there was a high correlation of standardised regression coefficients between the discovery and replication samples (r = 0.92). We found enrichment in biological processes involving metabolic activities and the Cytochrome P450 pathway. CYP2C19 metaboliser status did not interact with CYP2C19-related medication use to affect methylation of non-linear CpG signals.</p><p><strong>Conclusions: </strong>This research suggests that genetically-determined CYP2C19 metaboliser status is associated with both local and distal DNA methylation. These associations are independent of whether individuals were receiving drugs that are related to this enzyme.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-invasive epigenetic protein signatures associated with childhood obesity.","authors":"Erika M Richter, Priyadarshni Patel, Jeganathan R Babu, Thangiah Geetha","doi":"10.1186/s13148-026-02062-8","DOIUrl":"10.1186/s13148-026-02062-8","url":null,"abstract":"<p><strong>Background: </strong>Childhood obesity is a major predictor of lifelong chronic disease, yet the biological mechanisms linking early-life exposures to adiposity remain incompletely understood. Inflammatory and metabolic proteins have been implicated in obesity-related pathways, but their clinical utility in children is limited by biological variability and the invasiveness of sample collection. DNA methylation (DNAm)-derived protein proxies, or EpiScores, offer a stable, non-invasive alternative tool for capturing systemic physiological processes and may provide novel insights into the early biological embedding of obesity risk.</p><p><strong>Methods: </strong>We examined associations between 105 DNAm-derived protein EpiScores and body mass index (BMI) z-scores in a socioeconomically diverse cohort of 31 school-aged children. EpiScores were generated using the MethylDetectR platform, and linear regression models, adjusted for sex, age, race, saliva cell-type proportions, and socioeconomic status (SES; maternal education and annual household income), were used to evaluate associations. Parallel models excluding SES were compared to quantify confounding. False discovery rate (FDR) correction was applied. Functional enrichment and protein-protein interaction (PPI) analyses were performed using STRINGdB.</p><p><strong>Results: </strong>Fifteen EpiScores demonstrated nominal significance with BMI z-score (p ≤ 0.05) and were further evaluated using a discovery-level FDR threshold (FDR q ≤ 0.20). VEGFA, MMP-12, MMP-1, and CDL5 showed strong positive associations, while PAPP-A, Resistin, and TGF-α were inversely related to BMI z-score. Adjustment for socioeconomic status (SES) modestly altered several effect estimates, most notably for MMP-1 and CCL17, indicating partial social confounding. Functional enrichment revealed overrepresentation of cytokine-mediated signaling, extracellular matrix organization and angiogenesis pathways, highlighting coordinated immune, metabolic and vascular remodeling processes.</p><p><strong>Conclusions: </strong>Salivary DNAm-derived protein EpiScores capture biologically coherent and socially patterned molecular signatures of adiposity in children. These DNAm-based proxies provide a noninvasive means of detecting early alterations in metabolic regulation and may inform future longitudinal studies integrating biological and socioeconomic determinants of obesity risk.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"18 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147728748","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}