An interaction of the 17q12-21 locus with mold exposure in childhood asthma.
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ABSTRACT:
SUBMITTER: Lee S
PROVIDER: S-EPMC8277824 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.
| S-EPMC6172038 | biostudies-literature
Project description:Few studies address concurrent exposures to common household allergens, specific allergen sensitization and childhood asthma morbidity.To identify levels of allergen exposures that trigger asthma exacerbations in sensitized individuals.We sampled homes for common indoor allergens (fungi, dust mites (Der p 1, Der f 1), cat (Fel d 1), dog (Can f 1) and cockroach (Bla g 1)) for levels associated with respiratory responses among school-aged children with asthma (N=1233) in a month-long study. Blood samples for allergy testing and samples of airborne fungi and settled dust were collected at enrollment. Symptoms and medication use were recorded on calendars. Combined effects of specific allergen sensitization and level of exposure on wheeze, persistent cough, rescue medication use and a 5-level asthma severity score were examined using ordered logistic regression.Children sensitized and exposed to any Penicillium experienced increased risk of wheeze (odds ratio [OR] 2.12 95% confidence interval [CI] 1.12, 4.04), persistent cough (OR 2.01 95% CI 1.05, 3.85) and higher asthma severity score (OR 1.99 95% CI 1.06, 3.72) compared to those not sensitized or sensitized but unexposed. Children sensitized and exposed to pet allergen were at significantly increased risk of wheeze (by 39% and 53% for Fel d 1>0.12 ?g/g and Can f 1>1.2 ?g/g, respectively). Increased rescue medication use was significantly associated with sensitization and exposure to Der p 1>0.10 ?g/g (by 47%) and Fel d 1>0.12 ?g/g (by 32%).Asthmatic children sensitized and exposed to low levels of common household allergens Penicillium, Der p 1, Fel d 1 and Can f 1 are at significant risk for increased morbidity.
| S-EPMC3604733 | biostudies-literature
Project description:Genome-wide association studies (GWASes) revealed several single-nucleotide polymorphisms (SNPs) in the human 17q12-21 locus associated with autoimmune diseases. However, follow-up studies are still needed to identify causative SNPs directly mediating autoimmune risk in the locus. We have chosen six SNPs in high linkage disequilibrium with the GWAS hits that showed the strongest evidence of causality according to association pattern and epigenetic data and assessed their functionality in a local genomic context using luciferase reporter system. We found that rs12946510, rs4795397, rs12709365, and rs8067378 influenced the reporter expression level in leukocytic cell lines. The strongest effect visible in three distinct cell types was observed for rs12946510 that is predicted to alter MEF2A/C and FOXO1 binding sites.
| S-EPMC6409600 | biostudies-literature
Project description:BackgroundAfrican ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus.MethodsWe first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA).Findings17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [β] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (β 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLβ 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (β 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (β 1·29 [1·15-1·44], p<0·0001).InterpretationOur study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus.FundingNational Institutes of Health, Office of the Director.
| S-EPMC7335429 | biostudies-literature
Project description:BackgroundA number of studies have examined the association between mold exposure and childhood asthma. However, the conclusions were inconsistent, which might be partly attributable to the lack of consideration of gene function, especially the key genes affecting the pathogenesis of childhood asthma. Research on the interactions between genes and mold exposure on childhood asthma is still very limited. We therefore examined whether there is an interaction between inflammation-related genes and mold exposure on childhood asthma.MethodsA case-control study with 645 asthmatic children and 910 non-asthmatic children aged 3-12 years old was conducted. Eight single nucleotide polymorphisms (SNPs) in inflammation-related genes were genotyped using MassARRAY assay. Mold exposure was defined as self-reported visible mold on the walls. Associations between visible mold exposure, SNPs and childhood asthma were evaluated using logistic regression models. In addition, crossover analyses were used to estimate the gene-environment interactions on childhood asthma on an additive scale.ResultsAfter excluding children without information on visible mold exposure or SNPs, 608 asthmatic and 839 non-asthmatic children were included in the analyses. Visible mold exposure was reported in 151 asthmatic (24.8%) and 119 non-asthmatic children (14.2%) (aOR 2.19, 95% CI 1.62-2.97). The rs7216389 SNP in gasdermin B gene (GSDMB) increased the risk of childhood asthma with each C to T substitution in a dose-dependent pattern (additive model, aOR 1.32, 95% CI 1.11-1.57). Children carrying the rs7216389 T allele and exposed to visible mold dramatically increased the risk of childhood asthma (aOR 3.21; 95% CI 1.77-5.99). The attributable proportion due to the interaction (AP: 0.47, 95% CI 0.03-0.90) and the relative excess risk due to the interaction (RERI: 1.49, 95% CI 0-2.99) were statistically significant.ConclusionsIn the present study, there was a significant additive interaction between visible mold exposure and rs7216389 SNP on childhood asthma. Future studies need to consider the gene-environment interactions when exploring the risk factors of childhood asthma.
| S-EPMC8019181 | biostudies-literature
Project description:Epidemiological evidence on the relationship between single-nucleotide polymorphisms (SNPs) rs7216389 and rs11650680 on chromosome 17q12-21 and asthma is inconsistent. We examined this issue in young adult Japanese women. Case subjects were 202 women who had been diagnosed with asthma by a doctor, while 1290 women without doctor-diagnosed asthma served as control subjects. Adjustments were made for age and the presence of older siblings. There were no significant associations between SNP rs7216389 and asthma. Compared with the CC genotype of SNP rs11650680, the CT genotype, but not the TT genotype, was significantly inversely associated with asthma: the adjusted odds ratio for the CT genotype was 0.67 (95% confidence interval: 0.46-0.96). This inverse relationship was significant in women with late-onset asthma, but not in those with early-onset asthma. Under the dominant model, a significant inverse association was found between rs11650680 and asthma in women without older siblings, but not in those with older siblings; the interaction, however, was not significant. This is the first study to show that the CT genotype of SNP rs11650680 was significantly inversely associated with asthma, especially adult-onset asthma. We could not find evidence for interactions between rs11650680 and older siblings affecting asthma.
| S-EPMC4117259 | biostudies-literature
Project description:Phenotypic variation results from variation in gene expression, which is modulated by genetic and/or epigenetic factors. To understand the molecular basis of human disease, interaction between genetic and epigenetic factors needs to be taken into account. The asthma-associated region 17q12-q21 harbors three genes, the zona pellucida binding protein 2 (ZPBP2), gasdermin B (GSDMB) and ORM1-like 3 (ORMDL3), that show allele-specific differences in expression levels in lymphoblastoid cell lines (LCLs) and CD4+ T cells. Here, we report a molecular dissection of allele-specific transcriptional regulation of the genes within the chromosomal region 17q12-q21 combining in vitro transfection, formaldehyde-assisted isolation of regulatory elements, chromatin immunoprecipitation and DNA methylation assays in LCLs. We found that a single nucleotide polymorphism rs4795397 influences the activity of ZPBP2 promoter in vitro in an allele-dependent fashion, and also leads to nucleosome repositioning on the asthma-associated allele. However, variable methylation of exon 1 of ZPBP2 masks the strong genetic effect on ZPBP2 promoter activity in LCLs. In contrast, the ORMDL3 promoter is fully unmethylated, which allows detection of genetic effects on its transcription. We conclude that the cis-regulatory effects on 17q12-q21 gene expression result from interaction between several regulatory polymorphisms and epigenetic factors within the cis-regulatory haplotype region.
| S-EPMC3374122 | biostudies-literature
Project description:The evidence supporting an association between traffic-related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n?=?1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n?=?1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among air pollution exposure, methylation, and transcriptomic patterns.In the European cohorts, 186 SNPs had an interaction P?<?1?×?10-4 and a look-up evaluation of these disclosed 8 SNPs in 4 loci, with an interaction P?<?0.05 in the large CHS study, but not in CAPPS/SAGE. Three SNPs within adenylate cyclase 2 (ADCY2) showed the same direction of the interaction effect and were found to influence ADCY2 gene expression in peripheral blood (P?=?4.50?×?10-4). One other SNP with P?<?0.05 for interaction in CHS, rs686237, strongly influenced UDP-Gal:betaGlcNAc ?-1,4-galactosyltransferase, polypeptide 5 (B4GALT5) expression in lung tissue (P?=?1.18?×?10-17). Air pollution exposure was associated with differential discs, large homolog 2 (DLG2) methylation and expression.Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.
| S-EPMC5443897 | biostudies-literature
Project description:Most children diagnosed with asthma have respiratory symptoms such as cough, dyspnoea and wheezing, which are also important markers of overall respiratory function. A decade of genome-wide association studies (GWAS) have investigated genetic susceptibility to asthma itself, but few have focused on important respiratory symptoms that characterise childhood asthma.Using whole-genome sequencing (WGS) data for 894 asthmatic trios from a Costa Rican cohort, we performed family-based association tests (FBATs) to assess the association between genetic variants and multiple asthma-relevant respiratory phenotypes: cough, phlegm, wheezing, exertional dyspnoea and exertional chest tightness. We tested whether genome-wide significant associations were replicated in two additional studies: 1) 286 asthmatic trios from the Childhood Asthma Management Program (CAMP), and 2) 2691 African American current or former smokers from the COPDGene study.In the 894 Costa Rican trios, we identified a genome-wide significant association (p=2.16×10-9) between exertional dyspnoea and the single nucleotide polymorphism (SNP) rs10165869, located on chromosome 2q37.3, that was replicated in the CAMP cohort (p=0.023) with the same direction of association (combined p=3.28×10-10). This association was not found in the African American participants from COPDGene. We also found suggestive evidence for an association between SNP rs10165869 and the atypical chemokine receptor 3 (ACKR3).Our finding encourages the secondary association analysis of a wider range of phenotypes that characterise respiratory symptoms in other airway diseases/studies.
| S-EPMC8185954 | biostudies-literature
Project description:(1) Background: Variants of the interleukin-1 receptor antagonist (IL1RN) gene, encoding an anti-inflammatory cytokine, are associated with asthma. Asthma is a chronic inflammatory disease of the airway influenced by interactions between genetic variants and environmental factors. We discovered a gene-environment interaction (GEI) of IL1RN polymorphisms with childhood environmental tobacco smoke (ETS) exposure on asthma susceptibility in an urban adult population. (2) Methods: DNA samples from the NYU/Bellevue Asthma Registry were genotyped for tag SNPs in IL1RN in asthma cases and unrelated healthy controls. Logistic regressions were used to study the GEI between IL1RN variants and childhood ETS exposures on asthma and early onset asthma, respectively, adjusting for population admixture and other covariates. (3) Results: Whereas the rare genotypes of IL1RN SNPs (e.g., GG in SNP rs2234678) were associated with decreased risk for asthma among those without ETS exposure (odds ratio OR = 0.215, p = 0.021), they are associated with increased risk for early onset asthma among those with childhood ETS (OR = 4.467, p = 0.021). (4) Conclusions: We identified a GEI between polymorphisms of IL1RN and childhood ETS exposure in asthma. Analysis of GEI indicated that childhood ETS exposure disrupted the protective effect of some haplotypes/genotypes of IL1RN for asthma and turned them into high-risk polymorphisms for early onset asthma.
| S-EPMC7142766 | biostudies-literature