Homo sapiens
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ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-8052
PROVIDER: PRJNA100881 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma
2025-01-24 | E-GEOD-8052 | ExpressionAtlas
Project description:Asthma is caused by a combination of poorly understood genetic and environmental factors. We found multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in EBV-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P <10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encode transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Keywords: association study, global gene expression, asthma, ORMDL3
2007-07-01 | GSE8052 | GEO
Project description:Asthma is caused by a combination of poorly understood genetic and environmental factors. We found multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in EBV-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P <10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encode transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Experiment Overall Design: Gene expression levels were evaluated in 404 children. We then evaluated the relationship between SNPs in the 17q21 region (which show association to asthma in the same children) with gene expression levels. See http://www.sph.umich.edu/csg/liang/asthma/
2007-11-09 | E-GEOD-8052 | biostudies-arrayexpress
Project description:Asthma is characterized by intermittent inflammation of the airways, airflow limitation and wheeze. The ORMDL3 locus on chromosome 17q21 confers the major genetic susceptibility to childhood asthma. Although sphingolipids are important in immune signalling, the mechanisms of action of ORMDL3 on airway inflammation are incompletely understood. We used Affymetrix Human Gene 1.1 ST microarrays to detail the global effects of siRNA-mediated ORMDL3 knockdown during the time course of IL1B-induced inflammation in the A549 Human Lung Epithelial cell line.
2018-11-21 | GSE92484 | GEO
Project description:The human chromosomal region 17q12-q21 is associated with childhood asthma. It harbors 5 protein-coding genes, of which ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) and gasdermin B (GSDMB) are the top causal gene candidates. Emerging evidence suggests that the promoter region of another gene, the zona pellucida binding protein 2 (ZPBP2), located more than 50kb proximal to ORMDL3 may be critical for its transcriptional regulation influencing susceptibility to asthma. To test this hypothesis, we examined the lung phenotypes, liver transcriptomes and lipid metabolism of Zpbp2 knock-out (KO) mice. We found that in comparison to wild type (WT) mice, Zpbp2 KO mice sensitized with allergen ovalbumin (OVA) had reduced bronchial reactivity. The Zpbp2 KO mice also had altered lipid metabolism with a 3-fold decrease in the levels of docosahexaenoic acid (DHA), increased body weight and changes in the expression of the adipocytokine signaling pathway gene peroxisome proliferator activated receptor alpha (Pparα). The Zpbp2 deletion was also associated with increased DNA methylation at the Zpbp2 promoter/enhancer region, reminiscent of the methylation of the orthologous region in humans, and reduced expression of Ormdl3 in liver. The sum of our results implies that the Zpbp2 gene is involved in the regulation of airway hypersensitivity and lipid metabolism, either directly or through a cis-regulatory effect on Ormdl3.
2018-04-05 | GSE98513 | GEO
Project description:Background: Asthma is common chronic inflammatory disease of the airways with a heterogenous clinical presentation. Individual differences in asthma susceptibility remain poorly understood, although genetics is thought to play a major role. Aim: To build a polygenic risk score (PRS) for asthma and determine whether predictive genetic variants can be epigenomically linked to specific pathophysiological mechanisms. Methods: PRSs were constructed using data from genome-wide association studies and performance was validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14,926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and exacerbations. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from 14 primary cell types, including lung epithelial cells and T lymphocytes was used for epigenomic PRS partitioning. Results: All PRSs successfully predicted risk to develop asthma and related outcomes, with the strongest predictive power (2.42 odds ratios per PRS standard deviation, area under the curve of 0.736) achieved for childhood-onset asthma. PRSs allowed for stratification of the Rotterdam Study cohort into groups at low or high risk to develop asthma. PRS partitioning using genome-wide epigenomic profiles identified 5 clusters of variants within gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways. Conclusions: PRSs can predict whether individuals in a Dutch cohort developed asthma and asthma-related phenotypes, which is most effective for childhood-onset asthma. Importantly, we show that PRS partitioning based on epigenomics data dissects a genetic risk score into blocks of regulatory variants with differential predictive power, which likely represent distinct genetically driven disease pathways. These findings have potential implications for personalized risk mitigation and treatment strategies.
2024-07-03 | GSE245569 | GEO
Project description:Genetic and epigenetic determinants of neurogenesis and myogenesis [expression profiling]
2015-09-22 | E-GEOD-34907 | ExpressionAtlas
Project description:Family-Specific Genetic Variants Contributing to Asthma Susceptibility (FAstGen)
| PRJNA671152 | ENA
Project description:Recent genome-wide association studies (GWAS) have identified a number of novel genetic associations with complex human diseases. In spite of these successes, results from GWAS generally explain only a small proportion of disease heritability, an observation termed the M-bM-^@M-^\missing heritability problem.M-bM-^@M-^] Several sources for the missing heritability have been proposed, including the contribution of many common variants with small individual effect sizes, which cannot be reliably found using the standard GWAS approach. The goal of our study was to explore a complementary approach, which combines GWAS results with functional data in order to identify novel genetic associations with small effect sizes. To do so, we conducted a GWAS for lymphocyte count, a physiologic quantitative trait associated with asthma, in 462 Hutterites. In parallel, we performed a genome-wide gene expression study in lymphoblastoid cell lines (LCLs) from 96 Hutterites. We found significant support for genetic associations using the GWAS data when we considered variants near the 193 genes whose expression levels across individuals were most correlated with lymphocyte counts. Interestingly, these variants are also enriched with signatures of an association with asthma susceptibility, an observation we were able to replicate. The associated loci include genes previously implicated in asthma susceptibility, as well as novel candidate genes enriched for functions related to T cell receptor signaling and ATP synthesis. Our results, therefore, establish a new set of asthma susceptibility candidate genes. More generally, our observations support the notion that many loci of small effects influence variation in lymphocyte count and asthma susceptibility. 96 RNA samples were collected (1 subsequently excluded) from lymphoblastoid cell lines derived from Hutterite subjects chosen to represent the extremes of absolute lymphocyte count. The high and low absolute lymphocyte count groups were balanced with respect to age, gender, and relatedness.
2012-02-01 | E-GEOD-30697 | biostudies-arrayexpress
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature