Dataset Information

Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects.

ABSTRACT: The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex.Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive associations between these levels. A weighted correlation network analysis revealed that i) both transcriptome and methylome are organized in modules, ii) co-expression modules are generally not preserved in the methylation data and vice-versa, and iii) highly significant correlations exist between co-expression and co-methylation modules, suggesting the existence of factors that affect expression and methylation of different modules (i.e., trans effects at the level of modules). We observed that methylation probes associated with expression in cis were more likely to be located outside CpG islands, whereas specificity for CpG island shores was present when methylation, associated with expression, was under local genetic control. A structural equation model based analysis found strong support in particular for a traditional causal model in which gene expression is regulated by genetic variation via DNA methylation instead of gene expression affecting DNA methylation levels.Our results provide new insights into the complex mechanisms between genetic markers, epigenetic mechanisms and gene expression. We find strong support for the classical model of genetic variants regulating methylation, which in turn regulates gene expression. Moreover we show that, although the methylation and expression modules differ, they are highly correlated.

SUBMITTER: van Eijk KR

PROVIDER: S-EPMC3583143 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects.

van Eijk Kristel R KR de Jong Simone S Boks Marco P M MP Langeveld Terry T Colas Fabrice F Veldink Jan H JH de Kovel Carolien G F CG Janson Esther E Strengman Eric E Langfelder Peter P Kahn René S RS van den Berg Leonard H LH Horvath Steve S Ophoff Roel A RA

BMC genomics 20121117

<h4>Background</h4>The predominant model for regulation of gene expression through DNA methylation is an inverse association in which increased methylation results in decreased gene expression levels. However, recent studies suggest that the relationship between genetic variation, DNA methylation and expression is more complex.<h4>Results</h4>Systems genetic approaches for examining relationships between gene expression and methylation array data were used to find both negative and positive asso ...[more]

PMID: 23157493

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Project description:BackgroundEpigenetics, particularly DNA methylation, has recently been elucidated as important in gastric cancer (GC) initiation and progression. We investigated the clinical and prognostic importance of whole blood global and site-specific DNA methylation in GC.MethodsGenomic DNA was extracted from the peripheral blood of 105 Omani GC patients at diagnosis. DNA methylation was quantified by pyrosequencing of global DNA and specific gene promoter regions at 5 CpG sites for CDH1, 7 CpG sites for p16, 4 CpG sites for p53, and 3 CpG sites for RUNX3. DNA methylation levels in patients were categorized into low, medium, and high tertiles. Associations between methylation level category and clinicopathological features were evaluated using ?(2) tests. Survival analyses were carried out using the Kaplan-Meier method and log rank test. A backward conditional Cox proportional hazards regression model was used to identify independent predictors of survival.ResultsOlder GC patients had increased methylation levels at specific CpG sites within the CDH1, p53, and RUNX-3 promoters. Male gender was significantly associated with reduced global and increased site-specific DNA methylation levels in CDH1, p16, and p53 promoters. Global DNA low methylation level was associated with better survival on univariate analysis. Patients with high and medium methylation vs. low methylation levels across p16 promoter CpG sites, site 2 in particular, had better survival. Multivariate analysis showed that global DNA hypermethylation was a significant independent predictor of worse survival (hazard ratio (HR)?= 2.0, 95% CI: 1.1-3.8; p = 0.02) and high methylation mean values across p16 promoter sites 1-7 were associated with better survival with HR of 0.3 (95% CI, 0.1-0.8; p = 0.02) respectively.ConclusionsAnalysis of global and site-specific DNA methylation in peripheral blood by pyrosequencing provides quantitative DNA methylation values that may serve as important prognostic indicators.

Dataset Information

Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects.

Publications

Genetic analysis of DNA methylation and gene expression levels in whole blood of healthy human subjects.

Similar Datasets

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