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Primary human leukocyte RNA expression of unrelated Dutch and UK individuals

ABSTRACT: Multiple common variants for celiac disease influencing immune gene expression The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. We obtained peripheral blood RNA from unrelated Dutch and UK individuals using PAXgene tubes. We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10-4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5x10-8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression. *** Due to privacy concerns, the SNP data is not available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access directly from the submitter (contact info below). ***

ORGANISM(S): Homo sapiens

PROVIDER: GSE20332 | GEO | 2010/02/28

SECONDARY ACCESSION(S): PRJNA125399

REPOSITORIES: GEO

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Primary human leucocyte RNA expression of unrelated Dutch individuals.

Project description:Multiple common variants for celiac disease influencing immune gene expression The goal of this study was to study the effect of genetic variation on gene expression of untouched primary leucocytes. We obtained peripheral blood RNA from unrelated Dutch individuals using PAXgene tubes. We performed a second-generation genome wide association study of 4,533 celiac disease cases and 10,750 controls. We genotyped 113 selected SNPs with PGWAS<10-4, and 18 SNPs from 14 known loci, in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome wide significance (Pcombined<5x10-8), most contain immune function genes (BACH2, CCR4, CD80, CIITA/SOCS1/CLEC16A, ICOSLG, ZMIZ1) with ETS1, RUNX3, THEMIS and TNFRSF14 playing key roles in thymic T cell selection. A further 13 regions had suggestive association evidence. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P<0.0028, FDR 5%) with cis gene expression. *** Due to privacy concerns, the SNP data is not available with unrestricted access. Individuals wishing to obtain this data for research purposes may request access directly from the submitter (contact info below). ***

2010-02-28 | GSE20142 | GEO

Genome wide association study of Coeliac Disease

Project description:We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression

| EGAS00000000057 | EGA

Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease

Project description:The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.

2017-01-24 | GSE81881 | GEO

Different gene expression signatures in children and adults with celiac disease

Project description:We collected 19 duodenal biopsies of children and adults with celiac disease and compared the expression of 38 selected genes between each other and with the observed in 13 non-celiac disease controls matched by age. qPCR gene expression profiling. Intestinal samples from children and adults with active celiac disease patients and controls were analysed.

2015-12-19 | E-GEOD-76168 | biostudies-arrayexpress

Different gene expression signatures in children and adults with celiac disease

2015-12-19 | GSE76168 | GEO

Next Generation Sequencing analysis of IL-2 induced OT-I wild-type and OT-I Themis cKO cells for three days.

Project description:Thymocyte-expressed molecule involved in selection (Themis) was identified as a T cell-specific protein for T cell development. Recently, Themis was found to be required for T cell homeostasis by orchestrating TCR signaling and cytokine, especially γc family cytokine IL-7 signaling in peraphrial CD8+ T cells. Here, our study identifies Themis as a regulator for another γc family cytokine IL-2-induced proliferation. Transcriptomics and metabolomics reveal that Themis regulates Jak-Stat, Akt-mTOR as well as the downstream metabolic pathways. Moreover, how Themis regulates Shp1 phosphatase activity is still controversial. We further demonstrate that Themis negatively regulates Shp1 phosphatase activity on Jak1 and Jak3 to facilitate downstream signaling and subsequently metabolic reprograming, highlighting the importance of Themis in metabolic responses of CD8+ T cells.

2022-03-04 | GSE171315 | GEO

Gastrointestinal symptoms and pathology in patients with Common variable immunodeficiency

Project description:Based on the findings of increased IEL in duodenal biopsies in CVID, an overlap with celiac disease has been suggested. In the present study, increased IEL, in particular in the pars descendens of the duodenum, was one of the most frequent histopathological finding. We therefore examined the gene expression profile in pars descendens of duodenum in CVID patients with increased IEL (n=13, IEL mean 34 [range 22-56] IEL/100 EC), CVID with normal levels of IEL (n=7), celiac disease (n=10, Marsh grade 3a or above) and healthy controls (n=17) by gene expression microarray GI histopathological findings in 53 CVID patients that underwent upper and lower endoscopic examination were addressed. For the microarray analysis 20 CVID (7 CVID_normal and 13 CVID with incresed IEL), 10 patients with celiac diseases and 17 healthy controls were included.

2015-09-02 | E-GEOD-72625 | biostudies-arrayexpress

Altered thymic selection in Themis-deficient mice leads to expansion of an unusual virtual memory and bystander-competent CD8+ subpopulation bearing Va3.2 TCR

Project description:This study aimed to compare the TCRab repertoires from CD8 T cell subsets in a different T cell progression stage in Themis-sufficient and Themis-deficient mice. Analysis of the NGS-derived data revealed an overall reduction of the TCRa repertoire diversity in Themis's absence. In contrast, the CD8 compartment bearing the Va3.2 TCRs in the Themis-deficient model retains higher diversity than the repertoire from the Themis-sufficient counterpart. Furthermore, analysis of CDR3 peptide sequences of Va3.2+ and Va3.2- TCRs disclose the greater contribution of the hydrophobic residues in the former repertoires, indicating enhanced self-reactivity within this CD8+ T cell fraction.

2020-12-10 | GSE162963 | GEO

Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease

Project description:We use targeted bisulfite PCR and next-generation 454 sequencing of multiple amplicons to analyze the association of cis-regulated allele-specific methylation (ASM) with multiple complex disease-associated variants in a population of 82 individuals. We detect ASM at four variants implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn’s disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). 82 samples analysed

2014-07-01 | E-GEOD-56298 | biostudies-arrayexpress

Gene expression profiles of Themis-deficient thymocytes

Project description:Determine the biochemical cause of impaired development of Themis-deficient thymocytes. We isolated three thymocyte populations (three populations: CD4+CD8+CD5loCD69lo, CD4+CD8+CD5+CD69+, and CD4+CD8-CD24hiH2Klo) from Themis-deficient and WT mice. 8 or 9 individual biological replicates were analyzed for each population. An aliquot of cDNA from each sample was pooled and used as a reference.

2009-09-14 | E-GEOD-15246 | biostudies-arrayexpress

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