Genome-Wide Scan on Total Serum IgE Levels Identifies FCER1A as Novel Susceptibility Locus

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 x
10(-20) and 7.08 x 10(-19) in a combined analysis, and in a
post-hoc analysis showed additional associations with allergic
sensitization (P = 7.78 x 10(-4) and P = 1.95 x 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 x 10(-7)
-4.46 x 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.