Background Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association ...study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood. Methods We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis. Results CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 ( P = 1.5 × 10−12 ), ACOT7 ( P = 2.5 × 10−11 ), and MND1 ( P = 1.4 × 10−9 ). Conclusions In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children.
Background Bronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma. ...Objectives We sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma. Methods Whole-transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses. Results We found 90.2% overlap in expressed genes and strong correlation in gene expression (ρ = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (ρ = 0.77, P = 5.6 × 10−9 ). Clustering analysis identified TH 2-high and TH 2-low subjects differentiated by expression of 70 genes, including IL13 , IL5 , periostin (POSTN) , calcium-activated chloride channel regulator 1 (CLCA1) , and serpin peptidase inhibitor, clade B (SERPINB2) . TH 2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 × 10−6 ), atopic asthma (odds ratio, 32.6; P = 6.9 × 10−7 ), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 × 10−6 ), and rhinitis (odds ratio, 8.3; P = 4.1 × 10−6 ) compared with TH 2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year ( P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status. Conclusion Nasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13 -driven asthma and a TH 2-skewed systemic immune response.
Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We ...performed a genome-wide association study (GWAS) of FEV1 , forced vital capacity (FVC), and FEV1 /FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV1 /FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1 /FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 ( P = 5.7 × 10−8 to 3.4 × 10−9 ). Nine SNPs at or near 4 additional loci had P < 10−5 with FEV1 /FVC. Only 2 SNPs were found with P < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of β-defensin genes, 2 chemokine genes ( CCL18 and CXCL12 ), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.
Background The primary rescue medication to treat acute asthma exacerbation is the short-acting β2 -adrenergic receptor agonist; however, there is variation in how well a patient responds to ...treatment. Although these differences might be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator response (BDR). Objective To identify genetic variation associated with bronchodilator drug response in Latino children with asthma. Methods We performed a genome-wide association study (GWAS) for BDR in 1782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified 7 genetic variants associated with BDR at a genome-wide significant threshold ( P < 5 × 10−8 ), all of which had frequencies of less than 5%. Furthermore, we observed an excess of small P values driven by rare variants (frequency, <5%) and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified 5 significant peaks; fine mapping within these peaks identified 2 rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in SLC genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multiethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR.
Background IgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been ...well represented in genetic studies of total IgE. Objective We sought to identify the genetic predictors of serum total IgE levels. Methods We used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects. Results We identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels ( P < 5.0 × 10−6 ) and the minor allele frequency was 5% or greater in 2 or more population groups. Variant rs9469220, corresponding to HLA-DQB1 , was the single nucleotide polymorphism most significantly associated with serum total IgE levels when assessed in both the replication cohorts and the discovery and replication sets combined ( P = .007 and 2.45 × 10−7 , respectively). In addition, findings from earlier genome-wide association studies were also validated in the current meta-analysis. Conclusion This meta-analysis independently identified a variant near HLA-DQB1 as a predictor of total serum IgE levels in multiple race-ethnic groups. This study also extends and confirms the findings of earlier genome-wide association analyses in African American and Latino subjects.
First year of life exposures to NO2, PM10, PM2.5, or SO2 were not associated with atopic status (Table II). Experimental studies in those with asthma have shown that acute exposure to ozone ...stimulates airway neutrophilia,8,9 a characteristic though not necessarily a specific feature of asthma without sensitization. Because our analysis used data from a case-control study, our samples may not be representative of the underlying population or generalizable to the population of US Latinos.
Background Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations, and replication of positive ...associations has been inconsistent. Objective We sought to identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. Methods Latino children with asthma (n = 1893) and healthy control subjects (n = 1881) were recruited from 5 sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. Results We identified a significant association between ancestry and asthma at 6p21 (lowest P value: rs2523924, P < 5 × 10−6 ). This association replicates in a meta-analysis of the EVE Asthma Consortium ( P = .01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between SNPs in the 17q21 region and asthma in Latinos ( IKZF3 , lowest P value: rs90792, odds ratio, 0.67; 95% CI, 0.61-0.75; P = 6 × 10−13 ) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. Conclusions Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, whereas genome-wide association confirms the previously identified locus on 17q21.
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