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Title: Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment (dataset 1)      
dateReleased:
03-07-2014
description:
Medical research focuses on disease-specific genes. By contrast, here we systematically examined the roles of shared genes for disease susceptibility and as therapeutic and diagnostic targets. Meta-analysis of all published disease-related genome-wide association studies (GWAS) showed that T helper (Th) cell differentiation was the most shared pathway. Expression profiling data from highly diverse CD4+ T cell-associated diseases revealed shared disease-associated genes, which were enriched for Th cell differentiation, but also metabolic and proliferative pathways. This pleiotropy suggested that altered functions of shared genes could generally increase disease susceptibility. Indeed, compared to specific genes, the shared genes were enriched for disease-associated SNPs identified by all published disease-related GWAS. To examine if the shared genes induced disease-relevant pathways, we focused on transcription factors (TFs) that induced Th differentiation. Those TFs were enriched among the shared genes, as well as for disease-associated SNPs identified by GWAS, and disease-phenotypes in mice knock-out studies. Original GWAS and profiling data from patients with multiple sclerosis and allergy confirmed enrichment of disease-associated SNPs in the TFs, and that the TFs were differentially expressed at early disease stages, and their targets increased in parallel with disease development. From a clinical perspective, the shared genes were significantly enriched for known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed that shared or specific genes could be used to stratify patients for individualized medicine. Our findings show that shared disease genes generally increase disease susceptibility and are important therapeutic and diagnostic targets. Patients with seasonal allergic rhinitis (SAR) show considerable variations in response to glucocorticoids (GCs) treatment. Peripheral blood mononuclear cells (PBMCs) were collected from 8 high responders (HR) and 8 low responders (LR) to GC treatment. PBMCs were challenged with diluent, grass pollen extract (ALK-Abelló A/S; 100 μg/mL) as well as grass pollen extract plus glucocorticoids (100ug/mL) for one week. Total CD4+ T cells were enriched for the gene expression microarray analysis, which was performed using SurePrint G3 Human Gene Expression 8X60K microarrays.
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-44956
refinement:
raw
alternateIdentifiers:
44956
keywords:
functional genomics
dateModified:
06-02-2014
availability:
available
types:
gene expression
name:
Homo sapiens
ID:
A-GEOD-14550
name:
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Probe Name Version)
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-44956/E-GEOD-44956.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-44956/E-GEOD-44956.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE44956
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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