Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population

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.

Figure 1. Quantile-quantile (Q-Q) plot of observed versus expected P values of the GWAS results.

The straight line in the Q-Q plot indicates the distribution of SNPs under the null hypothesis.

Figure 2. Manhattan plots of −log₁₀ (P value) for association of 479,940 SNPs with total IgE levels.

Linear regression models adjusted for age, sex, smoking status (never, ex-, or current smoker), pack-year group (0, 0–10, or >10), and asthma affection status were performed. The red line shows the threshold (P = 1×10⁻⁵) for selection of genomic regions for further analysis including SNP imputation.

Figure 3. Fine-mapping identification of 6 candidate genomic regions.

Plots show the association results of both genotyped and imputed SNPs in the primary GWAS cohort. The most strongly associated SNPs (black letters) in the GWAS and the SNPs used for the replication studies (red letters) are indicated by arrows. The color of each circle reflects the LD (r²) between a particular SNP and the SNP used for the replication studies.