Abstract
High levels of serum IgE are considered markers of parasite and helminth exposure. In addition, they are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases. Total IgE is a strongly heritable trait. In a genome-wide association study (GWAS), we tested 353,569 SNPs for association with serum IgE levels in 1,530 individuals from the population-based KORA S3/F3 study. Replication was performed in four independent population-based study samples (total n = 9,769 individuals). Functional variants in the gene encoding the alpha chain of the high affinity receptor for IgE (FCER1A) on chromosome 1q23 (rs2251746 and rs2427837) were strongly associated with total IgE levels in all cohorts with P values of 1.85×10−20 and 7.08×10−19 in a combined analysis, and in a post-hoc analysis showed additional associations with allergic sensitization (P = 7.78×10−4 and P = 1.95×10−3). The “top” SNP significantly influenced the cell surface expression of FCER1A on basophils, and genome-wide expression profiles indicated an interesting novel regulatory mechanism of FCER1A expression via GATA-2. Polymorphisms within the RAD50 gene on chromosome 5q31 were consistently associated with IgE levels (P values 6.28×10−7−4.46×10−8) and increased the risk for atopic eczema and asthma. Furthermore, STAT6 was confirmed as susceptibility locus modulating IgE levels. In this first GWAS on total IgE FCER1A was identified and replicated as new susceptibility locus at which common genetic variation influences serum IgE levels. In addition, variants within the RAD50 gene might represent additional factors within cytokine gene cluster on chromosome 5q31, emphasizing the need for further investigations in this intriguing region. Our data furthermore confirm association of STAT6 variation with serum IgE levels.
Highlights
High levels of IgE have been considered for many years as markers of parasite and helminth exposure to which they confer resistance [1]
High levels of serum IgE are considered markers of parasite and helminth exposure. They are associated with allergic disorders, play a key role in anti-tumoral defence, and are crucial mediators of autoimmune diseases
There is strong evidence that the regulation of serum IgE levels is under a strong genetic control
Summary
High levels of IgE have been considered for many years as markers of parasite and helminth exposure to which they confer resistance [1]. In Western lifestyle countries with less contact, elevated IgE levels are associated with allergic disorders [2]. High total serum IgE levels are closely correlated with the clinical expression and severity of asthma and allergy [5,6]. The regulation of serum IgE production is largely influenced by familial determinants, and both pedigree- and twin-based studies provided evidence of a strong genetic contribution to the variability of total IgE levels [7,8]. Genetic susceptibility of IgEresponsiveness is likely to be caused by a pattern of polymorphisms in multiple genes regulating immunologic responses[9], but so far only very few loci could be established consistently and robustly, most notable FCER1B, IL-13 and STAT6 [10,11]
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