Abstract
Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10−10). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.
Highlights
Immunoglobulin E (IgE) is a class of antibodies that has an important role in the development of Th2 cell-mediated allergic inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis
In the MHC class I region, 4 genes have been previously reported to be associated with total serum IgE levels: HLA-A, HLA-G, LTA, and TNF [12,17,18,19,20,21,22]
Linkage disequilibrium (LD) between rs3130941 and each of these single nucleotide polymorphisms (SNPs) estimated by r2 in our population was very weak (Table S4, Figure S3)
Summary
Immunoglobulin E (IgE) is a class of antibodies that has an important role in the development of Th2 cell-mediated allergic inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis. Twin and family studies have shown that genetic factors are important for total serum IgE levels [3,4] and account for about 36% to 78% heritability of its levels [3,5]. A number of candidate gene association studies for total serum IgE levels have demonstrated many polymorphisms in genetic regions related to the Th2 cell-dependent pathways. 4 genome-wide association studies (GWASs) of total serum IgE levels in independent populations have revealed additional genetic loci, such as TBX18 and SOBP, which seem to be unrelated to the Th2 cell-dependent pathways [10,11,12,13]. 2 GWASs recently performed in Asian populations did not identify any loci significantly associated with total serum IgE levels [14,15]. We validated previously reported gene associations with total serum IgE levels using our GWAS data
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