Dataset Information

Association of asthma genetic variants with asthma-associated traits reveals molecular pathways of eosinophilic asthma.

ABSTRACT:

Introduction

Asthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome-wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma-associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs and asthma-associated traits and assess expression quantitative trait locus (e-QTLs) to reveal their downstream functional effects and find drug targets.

Methods

Association analyses between 128 asthma SNPs and associated traits (blood eosinophil numbers, atopy, airway obstruction, airway hyperresponsiveness) were conducted using regression modelling in population-based studies (Lifelines N = 32,817/Vlagtwedde-Vlaardingen N = 1554) and an asthma cohort (Dutch Asthma genome-wide association study N = 917). Functional enrichment and pathway analysis were performed with genes linked to the significant SNPs by e-QTL analysis. Genes were investigated to generate novel drug targets.

Results

We identified 69 asthma SNPs that were associated with at least one trait, with 20 SNPs being associated with multiple traits. The SNP annotated to SMAD3 was the most pleiotropic. In total, 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy. We identified genetically driven pathways regulating eosinophilia. The largest network of eosinophilia contained two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma. Several novel targets were identified such as IL-18, CCR4, and calcineurin.

Conclusion

Many asthma SNPs are associated with blood eosinophil counts and genetically driven molecular pathways of asthma-associated traits were identified.

SUBMITTER: El-Husseini ZW

PROVIDER: S-EPMC10119226 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Association of asthma genetic variants with asthma-associated traits reveals molecular pathways of eosinophilic asthma.

El-Husseini Zaid W ZW Vonk Judith M JM van den Berge Maarten M Gosens Reinoud R Koppelman Gerard H GH

Clinical and translational allergy 20230401 4

<h4>Introduction</h4>Asthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in genome-wide association studies. However, it is unknown if asthma SNPs are associated with specific asthma-associated traits such as high eosinophil counts, atopy, and airway obstruction, revealing molecular endotypes of this disease. Here, we aim to identify the association between asthma SNPs an ...[more]

PMID: 37186423

Similar Datasets

Project description:Background and objectiveObesity and asthma impose a heavy health and economic burden on millions of people around the world. The complex interaction between genetic traits and phenotypes caused the mechanism between obesity and asthma is still vague. This study investigates the relationship among obesity-related polygenic risk score (PRS), obesity phenotypes and the risk of having asthma.MethodsThis is a matched case-control study, with 4 controls (8288 non-asthmatic) for each case (2072 asthmatic). Data were obtained from the 2008-2015 Taiwan Biobank Database and linked to the 2000-2016 National Health Insurance Research Database. All participants were ≥30 years old with no history of cancer and had a complete questionnaire, as well as physical examination, genome-wide single nucleotide polymorphisms and clinical diagnosis data. Environmental exposure, PM2.5, was also considered. Multivariate adjusted ORs and 95% CIs were calculated using conditional logistic regression stratified by age and sex. Mediation analysis was also assessed, using a generalised linear model.ResultsWe found that the obese phenotype was associated with significantly increased odds of asthma by approximately 26%. Four obesity-related PRS, including body mass index (OR=1.07 (1.01-1.13)), waist circumference (OR=1.10 (1.04-1.17)), central obesity as defined by waist-to-height ratio (OR=1.09 (1.03-1.15)) and general-central obesity (OR=1.06 (1.00-1.12)), were associated with increased odds of asthma. Additional independent risk factors for asthma included lower educational level, family history of asthma, certain chronic diseases and increased PM2.5 exposure. Obesity-related PRS is an indirect risk factor for asthma, the link being fully mediated by the trait of obesity.ConclusionsObese phenotypes and obesity-related PRS are independent risk factors for having asthma in adults in the Taiwan Biobank. Overall, genetic risk for obesity increases the risk of asthma by affecting the obese phenotype.

Project description:BackgroundJuvenile idiopathic arthritis (JIA) is an autoimmune joint disease that frequently co-occurs with other complex phenotypes, including cancers and other autoimmune diseases. Despite the identification of numerous risk variants through genome-wide association studies (GWAS), the affected genes, their connection to JIA pathogenesis, and their role in the development of associated traits remain unclear. This study aims to address these gaps by elucidating the gene-regulatory mechanisms underlying JIA pathogenesis and exploring its potential role in the emergence of associated traits.MethodsA two-sample Mendelian Randomization (MR) analysis was conducted to identify blood-expressed genes causally linked to JIA. A curated protein interaction network was subsequently used to identify sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) that regulate the expression of JIA causal genes and their protein interaction partners. These SNPs were cross-referenced against the GWAS catalog to identify statistically enriched traits associated with JIA.ResultsThe two-sample MR analysis identified 52 genes whose expression changes in the blood are putatively causal for JIA. These genes (e.g., HLA, LTA, LTB, IL6ST) participate in a range of immune-related pathways (e.g., antigen presentation, cytokine signalling) and demonstrate cell type-specific regulatory patterns across different immune cell types (e.g., PPP1R11 in CD4+ T cells). The spatial eQTLs that regulate JIA causal genes and their interaction partners were statistically enriched for GWAS SNPs linked with 95 other traits, including both known and novel JIA-associated traits. This integrative analysis identified genes whose dysregulation may explain the links between JIA and associated traits, such as autoimmune/inflammatory diseases (genes at 6p22.1 locus), Hodgkin lymphoma (genes at 6p21.3 [FKBPL, PBX2, AGER]), and chronic lymphocytic leukemia (BAK1).ConclusionOur approach provides a significant advance in understanding the genetic architecture of JIA and associated traits. The results suggest that the burden of associated traits may differ among JIA patients, influenced by their combined genetic risk across different clusters of traits. Future experimental validation of the identified connections could pave the way for refined patient stratification, the discovery of new biomarkers, and shared therapeutic targets.

Project description:PurposeEosinophilic asthma (EA) and non-asthmatic eosinophilic bronchitis (EB) share similar eosinophilic airway inflammation. Unlike EA, EB did not present airway hyperresponsiveness or airflow obstruction. We aimed to compare the mechanism underlying the different manifestations between EA and EB via sputum transcriptomics analysis.MethodsInduced-sputum cells from newly physician-diagnosed EA, EB patients, and healthy controls (HCs) were collected for RNA sequencing.ResultsBulk RNA sequencing was performed using sputum cells from patients with EA (n = 18), EB (n = 15) and HCs (n = 28). Principal component analysis revealed similar gene expression patterns in EA and EB. The most differentially expressed genes in EB compared with HC were also shared by EA, including IL4, IL5 IL13, CLC, CPA3, and DNASE1L3. However, gene set enrichment analysis showed that the signatures regulating macrophage activation were enriched in EA compared to EB. Sputum cells were profiled using single-cell RNA sequencing. FABP4+ macrophages, SPP1+ macrophages, FCN1+ macrophages, dendritic cells, T cells, B cells, mast cells, and epithelial cells were identified based on gene expression profiling. Analysis of cell-cell communication revealed that interactions between FCN1+ macrophages and other cells were higher in EA than in EB. A wealth of transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF) interactions between FCN1+ macrophages and other cells have been shown in EA. The gene expression levels of EREG, TGFBI, and VEGFA in FCN1+ macrophages of EA were significantly higher than those of EB. Furthermore, signatures associated with the response to TGF-β, cellular response to VEGF stimulus and developmental cell growth were enriched in FCN1+ macrophages of EA compared to those of EB.ConclusionsFCN1+ macrophage activation associated with airway remodeling processes was upregulated in EA compared to that in EB, which may contribute to airway hyperresponsiveness and airflow obstruction.

Project description:The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)), hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)). Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

Dataset Information

Association of asthma genetic variants with asthma-associated traits reveals molecular pathways of eosinophilic asthma.

Introduction

Methods

Results

Conclusion

Publications

Association of asthma genetic variants with asthma-associated traits reveals molecular pathways of eosinophilic asthma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets