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Genome-wide peripheral blood leukocyte DNA methylation microarrays identified a single association with inflammatory bowel diseases.

ABSTRACT: Crohn's disease (CD) and ulcerative colitis (UC) are common forms of inflammatory bowel disease (IBD). Monozygotic (MZ) twin discordance rates and epidemiologic data implicate that environmental changes and epigenetic factors may play a pathogenic role in IBD. DNA methylation (the methylation of cytosines within CpG dinucleotides) is an epigenetic modification, which can respond to environmental influences. We investigated whether DNA methylation might be connected with IBD in peripheral blood leukocyte (PBL) DNA by utilizing genome-wide microarrays.Two different high-throughput microarray-based methods for genome-wide DNA methylation analysis were employed. First, DNA isolated from MZ twin pairs concordant (CD: 4; UC: 3) and discordant (CD: 4; UC: 7) for IBD was interrogated by a custom-made methylation-specific amplification microarray (MSAM). Second, the recently developed Illumina Infinium HumanMethylation450 BeadChip arrays were used on 48 samples of PBL DNA from discordant MZ twin pairs (CD: 3; UC: 3) and treatment-naive pediatric cases of IBD (CD: 14; UC: 8), as well as controls (n = 14). The microarrays were validated with bisulfite pyrosequencing.The MSAMs did not yield significant IBD associations. The Methylation BeadChip approach identified a single DNA methylation association of IBD at TEPP (testis, prostate and placenta-expressed protein) when DNA isolated selectively from peripheral blood mononuclear cells was analyzed (8.6% increase in methylation between CD and control, FDR = 0.0065).Microarray interrogation of IBD-dependent DNA methylation from PBLs appears to have limited ability to detect significant disease associations. More detailed and/or selective approaches may be useful for the elucidation of connections between the DNA methylome and IBD in the future.

SUBMITTER: Harris RA

PROVIDER: S-EPMC3812910 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Genome-wide peripheral blood leukocyte DNA methylation microarrays identified a single association with inflammatory bowel diseases.

Harris R Alan RA Nagy-Szakal Dorottya D Pedersen Natalia N Opekun Antone A Bronsky Jiri J Munkholm Pia P Jespersgaard Cathrine C Andersen PaalSkytt P Melegh Bela B Ferry George G Jess Tine T Kellermayer Richard R

Inflammatory bowel diseases 20120329 12

<h4>Background</h4>Crohn's disease (CD) and ulcerative colitis (UC) are common forms of inflammatory bowel disease (IBD). Monozygotic (MZ) twin discordance rates and epidemiologic data implicate that environmental changes and epigenetic factors may play a pathogenic role in IBD. DNA methylation (the methylation of cytosines within CpG dinucleotides) is an epigenetic modification, which can respond to environmental influences. We investigated whether DNA methylation might be connected with IBD in ...[more]

PMID: 22467598

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Project description:BackgroundIrritable bowel syndrome (IBS) is a stress-sensitive disorder. Environmental factors including stress can trigger epigenetic changes, which have not been well-studied in IBS. We performed a pilot study investigating genome-wide DNA methylation of IBS patients and healthy controls (HCs) to identify potential epigenetic markers and associated pathways. Additionally, we investigated relationships of epigenetic changes in selected genes with clinical traits.MethodsTwenty-seven IBS patients (59% women; 10 IBS-diarrhea, 8 IBS-constipation, 9 IBS-mixed) and 23 age- and sex-matched HCs were examined. DNA methylation from peripheral blood mononuclear cells (PBMCs) was measured using HM450 BeadChip, and representative methylation differences were confirmed by bisulphite sequencing. Gene expression was measured using quantitative PCR. Gastrointestinal (GI) and non-GI symptoms were measured using validated questionnaires. Associations were tested using non-parametric methods.Key resultsGenome-wide DNA methylation profiling of IBS patients compared with HCs identified 133 differentially methylated positions (DMPs) (mean difference ≥10%; p < 0.05). These genes were associated with gene ontology terms including glutathione metabolism related to oxidative stress and neuropeptide hormone activity. Validation by sequencing confirmed differential methylation of subcommissural organ (SCO)-Spondin (SSPO), glutathione-S-transferases mu 5 (GSTM5), and tubulin polymerization promoting protein genes. Methylation of two promoter CpGs in GSTM5 was associated with epigenetic silencing. Epigenetic changes in SSPO gene were positively correlated with hospital anxiety and depression scores in IBS patients (r > 0.4 and false discovery rate <0.05).Conclusions & inferencesThis study is the first to comprehensively explore the methylome of IBS patients. We identified DMPs in novel candidate genes which could provide new insights into disease mechanisms; however, these preliminary findings warrant confirmation in larger, independent studies.

Project description:BACKGROUND:Although many DNA methylation (DNAm) alterations observed in peripheral whole blood/leukocytes and serum have been considered as potential diagnostic markers for cancer, their origin and their specificity for cancer (e.g., vs inflammatory diseases) remain unclear. METHODS:From publicly available datasets, we identified changes in the methylation of blood-borne DNA for multiple cancers and inflammatory diseases. We compared the identified changes with DNAm difference between myeloid and lymphoid cells extracted from two datasets. RESULTS:At least 94.7% of the differentially methylated DNA loci (DM loci) observed in peripheral whole blood/leukocytes and serum of cancer patients overlapped with DM loci that distinguish between myeloid and lymphoid cells and >99.9% of the overlapped DM loci had consistent alteration states (hyper- or hypomethylation) in cancer samples compared to normal controls with those in myeloid cells compared to lymphoid cells (binomial test, P-value <2.2 × 10(-16)). Similar results were observed for DM loci in peripheral whole blood/leukocytes in patients with rheumatoid arthritis or inflammatory bowel diseases. The direct comparison between DM loci observed in the peripheral whole blood/leukocytes of patients with inflammatory diseases and DM loci observed in the peripheral whole blood of patients with cancer showed that DM loci detected from cancer and inflammatory diseases also had significantly consistent alteration states (binomial test, P-value <2.2 × 10(-16)). CONCLUSIONS:DNAm changes observed in the peripheral whole blood/leukocytes and serum of cancer patients and in the peripheral whole blood/leukocytes of inflammatory disease patients are predominantly determined by the increase of myeloid cells and the decrease of lymphoid cells under the disease conditions, in the sense that their alteration states in disease samples compared to normal controls mainly reflect the DNAm difference between myeloid and lymphoid cells. These analyses highlight the importance of comparing cancer and inflammatory disease directly for the identification of cancer-specific diagnostic biomarkers.

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Genome-wide peripheral blood leukocyte DNA methylation microarrays identified a single association with inflammatory bowel diseases.

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Genome-wide peripheral blood leukocyte DNA methylation microarrays identified a single association with inflammatory bowel diseases.

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