Clinical Epigenetics最新文献

{"title":"Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool.","authors":"Gleyson Francisco da Silva Carvalho, Claudio Melo de Gusmão, Beatriz Martins Wolff, Lucas Liro Vieira, Yanca Gasparini de Oliveira, Mariana Ribeiro Costa, Rafaela da Silva Mendes, Matheus Augusto Araujo Castro, Mayara T Sakuma, Fernando Kok, Bekim Sadikovic, Leslie Domenici Kulikowski","doi":"10.1186/s13148-024-01780-1","DOIUrl":"10.1186/s13148-024-01780-1","url":null,"abstract":"<p><strong>Background/objectives: </strong>KMT2B-related dystonia (DYT28, OMIM #617284) is a progressive neurological condition characterized by early onset movement disorders with autosomal dominant inheritance. In this study, we describe the use of a genome methylation episignature methodology to functionally validate two variants of uncertain significance (VUS) in the KMT2B gene.</p><p><strong>Methods: </strong>Genome-wide methylation status was assessed using the EPIC methylation assay in peripheral blood samples from two subjects with early onset movement disorder and missense variants of uncertain significance in the KMT2B gene (p.Leu1720Phe and p.Tyr2515Cys). After QC and normalization steps, we compared the M values for all 144 probes, previously described as an EpiSign for KMT2B-related dystonia, between the two subjects and 14 controls individuals.</p><p><strong>Results: </strong>The individual harboring the p.Tyr2515Cys variant exhibited a hypermethylation profile compatible with pathogenic/likely pathogenic variants in KMT2B, allowing for variant reclassification, conclusive genetic counseling, and patient stratification for deep brain stimulation. In contrast, the individual harboring the p.Leu1720Phe variant had a methylation status similar to controls, practically ruling out KMT2B-related dystonia.</p><p><strong>Conclusion: </strong>Investigation of methylation status can be a powerful tool to determine pathogenicity when facing KMT2B variants of uncertain significance. Methylation results may optimize genetic counseling and positively impact patient care.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"169"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715580","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":"Road traffic noise and breast cancer: DNA methylation in four core circadian genes.","authors":"Jesse D Thacher, Anastasiia Snigireva, Ulrike Maria Dauter, Mathilde N Delaval, Anna Oudin, Kristoffer Mattisson, Mette Sørensen, Signe Borgquist, Maria Albin, Karin Broberg","doi":"10.1186/s13148-024-01774-z","DOIUrl":"10.1186/s13148-024-01774-z","url":null,"abstract":"<p><strong>Background: </strong>Transportation noise has been linked with breast cancer, but existing literature is conflicting. One proposed mechanism is that transportation noise disrupts sleep and the circadian rhythm. We investigated the relationships between road traffic noise, DNA methylation in circadian rhythm genes, and breast cancer. We selected 610 female participants (318 breast cancer cases and 292 controls) enrolled into the Malmö, Diet, and Cancer cohort. DNA methylation of CpGs (N = 29) in regulatory regions of circadian rhythm genes (CRY1, BMAL1, CLOCK, and PER1) was assessed by pyrosequencing of DNA from lymphocytes collected at enrollment. To assess associations between modeled 5-year mean residential road traffic noise and differentially methylated CpG positions, we used linear regression models adjusting for potential confounders, including sociodemographics, shiftwork, and air pollution. Linear mixed effects models were used to evaluate road traffic noise and differentially methylated regions. Unconditional logistic regression was used to investigate CpG methylation and breast cancer.</p><p><strong>Results: </strong>We found that higher mean road traffic noise was associated with lower DNA methylation of three CRY1 CpGs (CpG1, CpG2, and CpG12) and three BMAL1 CpGs (CpG2, CpG6, and CpG7). Road traffic noise was also associated with differential methylation of CRY1 and BMAL1 promoters. In CRY1 CpG2 and CpG5 and in CLOCK CpG1, increasing levels of methylation tended to be associated with lower odds of breast cancer, with odds ratios (OR) of 0.88 (95% confidence interval (CI) 0.76-1.02), 0.84 (95% CI 0.74-0.96), and 0.80 (95% CI 0.68-0.94), respectively.</p><p><strong>Conclusions: </strong>In summary, our data suggest that DNA hypomethylation in CRY1 and BMAL1 could be part of a causal chain from road traffic noise to breast cancer. This is consistent with the hypothesis that disruption of the circadian rhythm, e.g., from road traffic noise exposure, increases the risk of breast cancer. Since no prior studies have explored this association, it is essential to replicate our results.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"168"},"PeriodicalIF":4.8,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715130","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":"Exploratory DNA methylation analysis in post-mortem heart tissue of sudden unexplained death.","authors":"Charlotte Sutter, Cordula Haas, Peter K Bode, Jacqueline Neubauer, Jeppe Dyrberg Andersen","doi":"10.1186/s13148-024-01777-w","DOIUrl":"10.1186/s13148-024-01777-w","url":null,"abstract":"<p><strong>Background: </strong>Sudden unexplained death (SUD) is a devastating event in the young. Despite efforts to identify causal genetic variants, many cases remain unexplained after genetic screening. This study aimed to investigate an alternative potential contributor to SUD by studying the human methylome using the MethylationEPIC v2.0 BeadChip kit in heart tissue from SUD cases. The genome-wide methylation results of the SUD cases were compared to the results of a control cohort. The SUD cases were divided into three main groups based on their autopsy reports, heart morphology and histopathology (primaryN: macroscopically and histologically normal heart; primaryCM: macroscopically or histologically abnormal heart, suspected cardiomyopathies; and secondary: myocardial damage due to other underlying conditions). The main focus of this study was to identify differentially methylated regions (DMRs) between the case groups and the control cohort.</p><p><strong>Results: </strong>We identified DMRs for both the primaryN and primaryCM groups, whereas the secondary group yielded no such results. In the primaryN cases, the corresponding genes for each DMR led to the identification of genes with common biological pathways. Some were associated with heart morphology (e.g. heart outflow tract morphogenesis or trabecular morphogenesis), but the majority belonged to more general cellular regulatory pathways (e.g. transcription coactivator activity, long non-coding RNAs, etc.). Although no common pathways were found for the primaryCM group, some common regulatory molecular functions were identified, such as p53 binding and transcription coactivator activity.</p><p><strong>Conclusions: </strong>Our study is the first to investigate the whole human methylome in heart tissue of SUD cases. We propose that there are observable differences in the methylation patterns of the case groups that may have contributed to SUD. Still, further studies are required to improve our understanding of the impact of methylation levels on SUD risk and to pinpoint methylation-based screening opportunities for SUD relatives.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"167"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692605","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":"Technical variability across the 450K, EPICv1, and EPICv2 DNA methylation arrays: lessons learned for clinical and longitudinal studies.","authors":"Alexandre A Lussier, Isabel K Schuurmans, Anna Großbach, Julie Maclsaac, Kristy Dever, Nastassja Koen, Heather J Zar, Dan J Stein, Michael S Kobor, Erin C Dunn","doi":"10.1186/s13148-024-01761-4","DOIUrl":"10.1186/s13148-024-01761-4","url":null,"abstract":"<p><p>DNA methylation (DNAm) is the most commonly measured epigenetic mechanism in human populations, with most studies using Illumina arrays to assess DNAm levels. In 2023, Illumina updated their DNAm arrays to the EPIC version 2 (EPICv2), building on prior iterations, namely the EPIC version 1 (EPICv1) and 450K arrays. Whether DNAm measurements are stable across these three generations of arrays has yet not been investigated, limiting the ability of researchers-especially those with longitudinal data-to compare and replicate results across arrays. Here, we present results from a study of 30 child participants (15 male; 15 female) from the Drakenstein Child Health Study, who had DNAm measured on all three of the latest arrays: 450K, EPICv1, and EPICv2. Using these data, we created an annotation of probe quality across arrays, which includes the intraclass correlations, interquartile ranges, correlations, and array bias (i.e., the extent to which DNAm levels were explained by array type) of all CpGs. We also present results from an analysis of sex differences, where we found that CpGs with lower replicability across arrays had higher array-based variance, suggesting this variance metric help guide replication efforts. We also showed that epigenetic age estimates across arrays were more stable when using the principal component versions of epigenetic clocks. Ultimately, this collection of results provides a framework for investigating the replicability and longitudinal stability of epigenetic changes across multiple versions of Illumina DNAm arrays.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"166"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692608","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":"Advances in the study of posttranslational modifications of histones in head and neck squamous cell carcinoma.","authors":"Yuyang Xiao, Yikai Zhang, Yuyang Hu, Xupeng Zhang, Jiaqi Tan, Shanhu Yao, Xingwei Wang, Yuexiang Qin","doi":"10.1186/s13148-024-01785-w","DOIUrl":"10.1186/s13148-024-01785-w","url":null,"abstract":"<p><p>The pathogenesis of head and neck squamous cell carcinoma (HNSCC) is notably complex. Early symptoms are often subtle, and effective early screening methods are currently lacking. The tumors associated with HNSCC develop rapidly, exhibit high aggressiveness, and respond poorly to existing treatments, leading to low survival rates and poor prognosis. Numerous studies have demonstrated that histone posttranslational modifications (HPTMs), including acetylation, methylation, phosphorylation, and ubiquitination, play a critical role in the occurrence and progression of HNSCC. Moreover, targeting histone posttranslationally modified molecules with specific drugs has shown potential in enhancing therapeutic outcomes and improving prognosis, underscoring their significant clinical value. This review aims to summarize the role of histone posttranslational modifications in the pathogenesis and progression of HNSCC and to discuss their clinical significance, thereby providing insights into novel therapeutic approaches and drug development for this malignancy.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"165"},"PeriodicalIF":4.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686136","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":"Cancer-associated fibroblasts reveal aberrant DNA methylation across different types of cancer.","authors":"Marco Schmidt, Tiago Maié, Thorsten Cramer, Ivan G Costa, Wolfgang Wagner","doi":"10.1186/s13148-024-01783-y","DOIUrl":"10.1186/s13148-024-01783-y","url":null,"abstract":"<p><strong>Background: </strong>Cancer-associated fibroblasts (CAFs) are essential components of the tumor microenvironment and play a critical role in cancer progression. Numerous studies have identified significant molecular differences between CAFs and normal tissue-associated fibroblasts (NAFs). In this study, we isolated CAFs and NAFs from liver tumors and conducted a comprehensive analysis of their DNA methylation profiles, integrating our finding with data from studies on other cancer types.</p><p><strong>Results: </strong>Our analysis revealed that several CAF samples exhibited aberrant DNA methylation patterns, which corresponded with altered gene expression levels. Notably, DNA methylation at liver CAF-specific CpG sites was linked to survival outcomes in liver cancer datasets. An integrative analysis using publicly available datasets from various cancer types, including lung, prostate, esophageal, and gastric cancers, uncovered common epigenetic abnormalities across these cancers. Among the consistently altered CpGs were cg09809672 (EDARADD), cg07134930 (HDAC4), and cg05935904 (intergenic). These methylation changes were associated with prognosis across multiple cancer types.</p><p><strong>Conclusion: </strong>The activation of CAFs by the tumor microenvironment seems to be associated with distinct epigenetic modifications. Remarkably, similar genomic regions tend to undergo hypomethylation in CAFs across different studies and cancer types. Our findings suggest that CAF-associated DNA methylation changes hold potential as prognostic biomarkers. However, further research and validation are necessary to develop and apply such signatures in a clinical setting.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"164"},"PeriodicalIF":4.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680999","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":"Associations of epigenetic age acceleration at birth and age 12 years with adolescent cardiometabolic risk: the HOME study.","authors":"Jennifer L Arzu, Karl T Kelsey, George D Papandonatos, Kim M Cecil, Aimin Chen, Scott M Langevin, Bruce P Lanphear, Kimberly Yolton, Jessie P Buckley, Joseph M Braun","doi":"10.1186/s13148-024-01779-8","DOIUrl":"10.1186/s13148-024-01779-8","url":null,"abstract":"<p><strong>Background: </strong>Cardiometabolic risk factors among youth are rising. Epigenetic age acceleration, a biomarker for aging and disease-risk, has been associated with adiposity in children, but its association with other cardiometabolic risk markers remains understudied. We employed data from the Health Outcomes and Measures of the Environment (HOME) study, a prospective pregnancy and birth cohort in the greater Cincinnati metropolitan area, to examine whether accelerated epigenetic age at birth as well as accelerated epigenetic age and faster pace of biological aging at age 12 years were associated with higher cardiometabolic risk in adolescents.</p><p><strong>Results: </strong>After adjusting for potential confounders, including estimated cell type proportions, epigenetic gestational age acceleration at birth, derived from the Bohlin, Knight, and Haftorn clocks using cord blood DNA methylation data, was not associated with cardiometabolic risk z-scores or individual cardiometabolic risk score components (visceral fat, leptin to adiponectin ratio, HOMA-IR, triglycerides to HDL-C ratio, HbA1c, or systolic blood pressure) at age 12 years. We also did not observe any associations of epigenetic age acceleration, calculated with Horvath's skin and blood, Hannum's, and Wu's epigenetic clocks using peripheral blood at age 12 years, with these same cardiometabolic risk markers. In contrast, faster pace of biological aging was associated with higher cardiometabolic risk [βs (95% CIs)] cardiometabolic risk score 0.25 (0.07, 0.42); visceral fat 0.21 (0.05, 0.38); and hemoglobin A1c 0.23 (0.05, 0.41) per standard deviation increase in pace of biological aging. Faster pace of biological aging was also positively associated with systolic blood pressure, triglycerides to HDL-C ratio, HOMA-IR, and leptin to adiponectin ratio, although these associations were not statistically significant.</p><p><strong>Conclusions: </strong>Our findings provide evidence that faster pace of biological aging was associated with higher cardiometabolic risk score, visceral fat, and HbA1c at age 12 years. Further research is needed to determine whether these associations persist from adolescence through adulthood.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"163"},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675358","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 modifications involving ncRNAs in digestive system cancers: focus on histone modification.","authors":"Xiaodi Yin, Jingyi Li, Jiahui Zhao, Weihan Zheng, Aohua Zhang, Jun Ma","doi":"10.1186/s13148-024-01773-0","DOIUrl":"10.1186/s13148-024-01773-0","url":null,"abstract":"<p><p>In recent years, epigenetic modifications have been strongly linked to tumor development, with histone modifications representing a key epigenetic mechanism. In addition, non-coding RNAs (ncRNAs) play a critical role in regulating cancer-related pathways. The abnormal interaction between histone modifications and ncRNAs, both pivotal epigenetic regulators, has been widely observed across various cancer types. Here, we systematically explore the molecular mechanisms through which histone modifications and ncRNAs contribute in the pathogenesis of digestive system cancers, and aberrant ncRNA-mediated histone modifications manipulate various biological behaviors of tumor cells including proliferation, migration, angiogenesis, etc. In addition, we provide new insights into diagnostic, prognostic markers, therapeutic targets and chemoradiation resistance for digestive system cancers from the epigenetic perspective.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"162"},"PeriodicalIF":4.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675364","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":"Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk factors.","authors":"Hannes Frederik Bode, Liang He, Jacob V B Hjelmborg, Jaakko Kaprio, Miina Ollikainen","doi":"10.1186/s13148-024-01767-y","DOIUrl":"10.1186/s13148-024-01767-y","url":null,"abstract":"<p><strong>Background: </strong>Assessment of breast cancer (BC) risk generally relies on mammography, family history, reproductive history, and genotyping of major mutations. However, assessing the impact of environmental factors, such as lifestyle, health-related behavior, or external exposures, is still challenging. DNA methylation (DNAm), capturing both genetic and environmental effects, presents a promising opportunity. Previous studies have identified associations and predicted the risk of BC using DNAm in blood; however, these studies did not distinguish between genetic and environmental contributions to these DNAm sites. In this study, associations between DNAm and BC are assessed using paired twin models, which control for shared genetic and environmental effects, allowing testing for associations between DNAm and non-shared environmental exposures and behavior.</p><p><strong>Results: </strong>Pre-diagnosis blood samples of 32 monozygotic (MZ) and 76 dizygotic (DZ) female twin pairs discordant for BC were collected at the mean age of 56.0 years, with the mean age at diagnosis 66.8 years and censoring 75.2 years. We identified 212 CpGs (p < 6.4*10^-8) and 15 DMRs associated with BC risk across all pairs using paired Cox proportional hazard models. All but one of the BC risks associated with CpGs were hypomethylated, and 198/212 CpGs had their DNAm associated with BC risk independent of genetic effects. According to previous literature, at least five of the top CpGs were related to estrogen signaling. Following a comprehensive two-sample Mendelian randomization analysis, we found evidence supporting a dual causal impact of DNAm at cg20145695 (gene body of NXN, rs480351) with increased risk for estrogen receptor positive BC and decreased risk for estrogen receptor negative BC.</p><p><strong>Conclusion: </strong>While causal effects of DNAm on BC risk are rare, most of the identified CpGs associated with the risk of BC appear to be independent of genetic effects. This suggests that DNAm could serve as a valuable biomarker for environmental risk factors for BC, and may offer potential benefits as a complementary tool to current risk assessment procedures.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"160"},"PeriodicalIF":4.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667454","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":"MOSES: a methylation-based gene association approach for unveiling environmentally regulated genes linked to a trait or disease.","authors":"Soyeon Kim, Yidi Qin, Hyun Jung Park, Rebecca I Caldino Bohn, Molin Yue, Zhongli Xu, Erick Forno, Wei Chen, Juan C Celedón","doi":"10.1186/s13148-024-01776-x","DOIUrl":"10.1186/s13148-024-01776-x","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation is a critical regulatory mechanism of gene expression, influencing various human diseases and traits. While traditional expression quantitative trait loci (eQTL) studies have helped elucidate the genetic regulation of gene expression, there is a growing need to explore environmental influences on gene expression. Existing methods such as PrediXcan and FUSION focus on genotype-based associations but overlook the impact of environmental factors. To address this gap, we present MOSES (methylation-based gene association), a novel approach that utilizes DNA methylation to identify environmentally regulated genes associated with traits or diseases without relying on measured gene expression.</p><p><strong>Results: </strong>MOSES involves training, imputation, and association testing. It employs elastic-net penalized regression models to estimate the influence of CpGs and SNPs (if available) on gene expression. We developed and compared four MOSES versions incorporating different methylation and genetic data: (1) cis-DNA methylation within 1 Mb of promoter regions, (2) both cis-SNPs and cis-CpGs, 3) both cis- and a part of trans- CpGs (±5Mb away) from promoter regions), and 4) long-range DNA methylation (±10 Mb away) from promoter regions. Our analysis using nasal epithelium and white blood cell data from the Epigenetic Variation and Childhood Asthma in Puerto Ricans (EVA-PR) study demonstrated that MOSES, particularly the version incorporating long-range CpGs (MOSES-DNAm 10 M), significantly outperformed existing methods like PrediXcan, MethylXcan, and Biomethyl in predicting gene expression. MOSES-DNAm 10 M identified more differentially expressed genes (DEGs) associated with atopic asthma, particularly those involved in immune pathways, highlighting its superior performance in uncovering environmentally regulated genes. Further application of MOSES to lung tissue data from idiopathic pulmonary fibrosis (IPF) patients confirmed its robustness and versatility across different diseases and tissues.</p><p><strong>Conclusion: </strong>MOSES represents an innovative advancement in gene association studies, leveraging DNA methylation to capture the influence of environmental factors on gene expression. By incorporating long-range CpGs, MOSES-DNAm 10 M provides superior predictive accuracy and gene association capabilities compared to traditional genotype-based methods. This novel approach offers valuable insights into the complex interplay between genetics and the environment, enhancing our understanding of disease mechanisms and potentially guiding therapeutic strategies. The user-friendly MOSES R package is publicly available to advance studies in various diseases, including immune-related conditions like asthma.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"161"},"PeriodicalIF":4.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11574994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667453","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}