DAC for genome-wide association study of prognosis in Crohn's disease
Ontology highlight
ABSTRACT:
PROVIDER: EGAC00001000568 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Genome-wide association study of prognosis in Crohn's disease
| EGAS00001002147 | EGA
Project description:For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
| S-EPMC5730041 | biostudies-literature
Project description:Morphological patterns of Paneth cells are a cellular biomarker in western Crohn’s disease (CD) patients. They integrate genetics and environmental factors, and are associated with outcomes. To broaden the applications of Paneth cell phenotype, identification of novel genetic determinants and clinical validation in other ethnic groups is critical.
2017-08-22 | GSE90102 | GEO
Project description:NIDDK IBD Genetics Consortium Crohn's Disease Genome-Wide Association Study
| PRJNA75429 | ENA
Project description:BackgroundThe use of biological annotation such as genes and pathways in the analysis of gene expression data has aided the identification of genes for follow-up studies and suggested functional information to uncharacterized genes. Several studies have applied similar methods to genome wide association studies and identified a number of disease related pathways. However, many questions remain on how to best approach this problem, such as whether there is a need to obtain a score to summarize association evidence at the gene level, and whether a pathway, dominated by just a few highly significant genes, is of interest.MethodsWe evaluated the performance of two pathway-based methods (Random Set, and Binomial approximation to the hypergeometric test) based on their applications to three data sets of Crohn's disease. We consider both the disease status as a phenotype as well as the residuals after conditioning on IL23R, a known Crohn's related gene, as a phenotype.ResultsOur results show that Random Set method has the most power to identify disease related pathways. We confirm previously reported disease related pathways and provide evidence for IL-2 Receptor Beta Chain in T cell Activation and IL-9 signaling as Crohn's disease associated pathways.ConclusionsOur results highlight the need to apply powerful gene score methods prior to pathway enrichment tests, and that controlling for genes that attain genome wide significance enable further biological insight.
| S-EPMC2908056 | biostudies-literature
Project description:Over the course of the past decade, genome-wide association studies (GWAS) have revolutionised our understanding of complex disease genetics. One of the diseases that has benefitted most from this technology has been Crohn's disease (CD), with the identification of autophagy, the IL-17/IL-23 axis and innate lymphoid cells as key players in CD pathogenesis. Our increasing understanding of the genetic architecture of CD has also highlighted how a failure to suppress aberrant immune responses may contribute to disease development - a realisation that is now being incorporated into the design of new treatments. However, despite these successes, a significant proportion of disease heritability remains unexplained. Similarly, most of the causal variants at associated loci have not yet been identified, and even fewer have been functionally characterised. Because of the inarguable rise in the incidence of CD in regions of the world that previously had low disease rates, GWAS studies will soon have to shift from a largely Caucasian focus to include populations from other ethnic backgrounds. Future studies should also move beyond conventional studies of disease susceptibility into phenotypically driven 'within-cases' analyses in order to explore the role of genetics in other important aspects of disease biology. These studies are likely to include assessments of prognosis and/or response to treatments and may be critical if personalised medicine is ever to become a reality.
| S-EPMC5822399 | biostudies-literature
Project description:Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.
| S-EPMC1965486 | biostudies-literature
Project description:Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.
| S-EPMC2574810 | biostudies-literature
Project description:Reversal of gene promoter DNA hypermethylation and associated abnormal gene silencing is an attractive approach to cancer therapy. The DNA methylation inhibitor, decitabine (5-aza-2'-deoxycitidine), is proving efficacious for hematological neoplasms especially at lower, less toxic, doses. Experimentally, high doses induce rapid DNA damage and cytotoxicity, but these may not explain the prolonged time to response seen in patients. Transient exposure of leukemic and solid tumor cells to clinically-relevant nanomolar doses, without causing immediate cytotoxicity or apoptosis, produces sustained reduced tumorigenicity, and for leukemia cells, diminished long-term self-renewal. These effects appear triggered by cellular reprogramming and include sustained decreases in promoter DNA methylation with associated gene re-expression, and anti-tumor changes in multiple key cellular regulatory pathways, most of which are high priority targets for pharmacologic anti-cancer strategies. Thus, low dose decitabine regimens appear to have broad applicability for cancer management. [Gene expression profiling] Leukemia cell lines Kasumi-1 and KG1A are treated with 10nM DAC during 72 hours and gene expression was assayed at day 3, 7 and 14 after the start of the treatment. Appropriate mock treated samples were used as control in each case. In addition, Kasumi-1 cells were also treated with a higher dose of DAC (500nM), 100nM ARA-C and 300 nM TSA, again controlled against mock treated Kasumi-1 cells, to separate dose and agent dependent effects. MCF7 was studied as an example of a solid tumor cell line. Therefore MCF7 cells were treated with 100nM DAC and results were assayed at day 1, day 3 and day 10. [Methylation profiling] The effects of the demethylating agent DAC were studied in the leukemia cell line Kasumi-1 over a 28 day time course. Intermediate time points were studied at days 3, 7, 14 and 21. These results were verfied in KG1A and KG1 leukemia cell lines, at one selected time point. The effects on one primary sample were also studied. Four normal leukemia samples (PL1, 2, 4 and 5) were used as general controls. The effect of DAC was compared to ARA-C, TSA. Both mock treated and day 3 DAC treated Kasumi-1 cells were repeated. These results were verified at one selected time point for the DAC treated MCF7 breast cancer cell line.
2012-03-21 | E-GEOD-20945 | biostudies-arrayexpress
Project description:BACKGROUND:Traditional clinicopathologic features of breast cancer do not account for all the variation in survival. Germline genetic variation may provide additional prognostic information. MATERIALS AND METHODS:We conducted a genome-wide association study of survival after a diagnosis of breast cancer by obtaining follow-up data and genotyping information on 528,252 single-nucleotide polymorphisms for 1,145 postmenopausal women with invasive breast cancer (7,711 person-years at risk) from the Nurses' Health Study scanned in the Cancer Genetic Markers of Susceptibility initiative. We genotyped the 10 most statistically significant loci (most significant single-nucleotide polymorphism located in ARHGAP10; P = 2.28 x 10(-7)) in 4,335 women diagnosed with invasive breast cancer (38,148 years at risk) in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. RESULTS:None of the loci replicated in the SEARCH study (all P > 0.10). Assuming a minimum of 10 associated loci, the power to detect at least one with a minor allele frequency of 0.2 conferring a relative hazard of 2.0 at genome-wide significance (P = 5 x 10(-8)) was 99%. CONCLUSION:We did not identify any common germline variants associated with breast cancer survival overall. IMPACT:Our data suggest that it is unlikely that there are common germline variants with large effect sizes for breast cancer survival overall (hazard ratio >2). Instead, it is plausible that common variants associated with survival could be specific to tumor subtypes or treatment approaches. New studies, sufficiently powered, are needed to discover new regions associated with survival overall or by subtype or treatment subgroups.
| S-EPMC2852476 | biostudies-literature