Integrative Epigenome-Wide Analysis Shows That DNA Methylation May Mediate Genetic Risk In Inflammatory Bowel Disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE87650 | GEO | 2016/11/13
SECONDARY ACCESSION(S): PRJNA345569
REPOSITORIES: GEO
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Project description:Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2, TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two genetic polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data highlight the cell type of origin of epigenetic signals seen in whole blood; IBD-associated hypermethylation within the TXK gene transcription start-sitepromoter region negatively correlates with gene expression in whole blood and CD8+ T-cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD are relatedrelate to underlying genotype and associate with cell-specific alteration in gene expression.
2016-11-13 | GSE87640 | GEO
Project description:Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2, TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two genetic polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data highlight the cell type of origin of epigenetic signals seen in whole blood; IBD-associated hypermethylation within the TXK gene transcription start-sitepromoter region negatively correlates with gene expression in whole blood and CD8+ T-cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD are relatedrelate to underlying genotype and associate with cell-specific alteration in gene expression.
2016-11-13 | GSE86434 | GEO
Project description:Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
| S-EPMC5133631 | biostudies-literature
Project description:Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2, TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two genetic polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data highlight the cell type of origin of epigenetic signals seen in whole blood; IBD-associated hypermethylation within the TXK gene transcription start-sitepromoter region negatively correlates with gene expression in whole blood and CD8+ T-cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD are relatedrelate to underlying genotype and associate with cell-specific alteration in gene expression.
2016-11-13 | GSE87648 | GEO
Project description:Integrative Epigenome-Wide Analysis Shows That DNA Methylation May Mediate Genetic Risk In Inflammatory Bowel Disease
| PRJNA345569 | ENA
Project description:Background and aimsInflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes.MethodsClinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n = 1097; cohort B, n = 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B.ResultsCrohn's disease [CD] GRS were associated with fibrostenotic CD [R2 = 7.4%, FDR = 0.02] and ileocaecal resection [R2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R2 = 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R2 = 1.7%, FDR = 0.04].ConclusionsPatients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.
| S-EPMC8218708 | biostudies-literature
Project description:inflammatory bowel disease Raw sequence reads
| PRJNA943357 | ENA
Project description:To date, the utility of single genetic markers to improve disease risk assessment still explains only a small proportion of genetic variance for many complex diseases. This missing heritability may be explained by additional variants with weak effects. To discover and incorporate these additional genetic factors, statistical and computational methods must be evaluated and developed. We develop a multi-locus genetic risk score (GRS) based approach to analyze genes in NADPH oxidase complex which may result in susceptibility to development of inflammatory bowel disease (IBD). We find the complex is highly associated with IBD (P = 7.86 × 10(-14)) using the GRS-based association method. Similar results are also shown in permutation analysis (P = 6.65 × 10(-11)). Likelihood ratio test shows that the single nucleotide polymorphisms (SNPs) in the complex without nominal signals have significant contribution to the overall genetic effect within the complex (P = 0.015). Our results show that the multi-locus GRS association model can improve the genetic risk assessment on IBD by taking into account both confirmed and as yet unconfirmed disease susceptibility variants.
| S-EPMC3662393 | biostudies-literature
Project description:BackgroundDespite recent advances the majority of inflammatory bowel disease (IBD) susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens.MethodsWe genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls.ResultsThe most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002).ConclusionsThese findings support the significance of the epithelial barrier in IBD pathogenesis.
| S-EPMC2614310 | biostudies-literature
Project description:Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.
| S-EPMC4172734 | biostudies-literature