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.

Figure 1

Manhattan plot of the genome wide association results for serum total IgE from the meta-analysis. The significance level used to promote single nucleotide polymorphisms for replication (P < 5.0 × 10⁻⁶) is denoted by the dashed line. The solid line shows the genome wide significance level of P < 5.0 × 10⁻⁸.

Figure 2

Locus zoom plots of rs9469220 (triangle) located between HLA-DQB1 and HLA-DQA2 on chromosome 6 and its association with serum total IgE levels. The plots show the association P-values (derived from the genome wide meta-analysis) and the linkage disequilibrium (with rs9469220) in color for the surrounding single nucleotide polymorphisms in European American individuals (A), African American individuals (B), and Latino individuals (C). The polymorphism near HLA-DQA2, rs2858331, identified by Granada et al.⁽⁴⁷⁾ is also shown (square).