A meta-analysis of genome-wide association studies for serum total IgE in diverse study populations.
ABSTRACT 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.
Article: Genetics of Allergic Diseases[Show abstract] [Hide abstract]
ABSTRACT: Genome-wide association studies (GWAS) have been employed in the field of allergic disease, and significant associations have been published for nearly 100 asthma genes/loci. An outcome of GWAS in allergic disease has been the formation of national and international collaborations leading to consortia meta-analyses, and an appreciation for the specificity of genetic associations to sub-phenotypes of allergic disease. Molecular genetics has undergone a technological revolution, leading to next-generation sequencing strategies that are increasingly employed to hone in on the causal variants associated with allergic diseases. Unmet needs include the inclusion of diverse cohorts and strategies for managing big data. Copyright © 2015 Elsevier Inc. All rights reserved.Immunology and Allergy Clinics of North America 11/2014; 35(1). DOI:10.1016/j.iac.2014.09.014 · 2.22 Impact Factor
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ABSTRACT: An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased samples sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities.This article is protected by copyright. All rights reserved.Clinical & Experimental Allergy 04/2014; 45(1). DOI:10.1111/cea.12327 · 4.32 Impact Factor
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ABSTRACT: Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies (GWAS) in 2653 male asthma cases, 2566 female asthma cases, and 3830 non-asthma controls from European American, African American, African Caribbean, and Latino populations. Association tests were conducted in each study sample and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had p-values <1x10(-6), of which two were male-specific and four were female-specific; all were ancestry-specific. The most significant sex-specific association in European Americans was at the IRF1 locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single nucleotide polymorphisms (SNPs) that are known expression quantitative trait loci (eQTLs) and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways, and prior reports of sex-specific differences in interferon responses.Human Molecular Genetics 05/2014; DOI:10.1093/hmg/ddu222 · 6.68 Impact Factor