An epigenome-wide association study of total serum IgE in Hispanic children

Abstract

Background: Total IgE is a therapeutic target in patients with allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE levels in an epigenome-wide association study of white subjects. Whether DNA methylation of eosinophils explains these findings is insufficiently understood.

Methods: We tested for association between genome-wide DNA methylation in WBCs and total IgE levels in 2 studies of Hispanic children: the Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL; n = 306) and the Genes-environments and Admixture in Latino Americans (GALA II) study (n = 573). Whole-genome methylation of DNA from WBCs was measured by using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE levels were measured by using the UniCAP 100 system. In PR-GOAL WBC types (ie, neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured by using Coulter Counter techniques. In the GALA II study WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE levels, which was first conducted separately for each cohort, and then results from the 2 cohorts were combined in a meta-analysis.

Results: CpG sites in multiple genes, including novel findings and results previously reported in white subjects, were significantly associated with total IgE levels. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in the genes ZFPM1 (P = 1.5 × 10^-12), ACOT7 (P = 2.5 × 10^-11), and MND1 (P = 1.4 × 10^-9).

Conclusions: In an epigenome-wide association study adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE levels among Hispanic children.

Keywords: Epigenome-wide association study; Hispanic; children; total IgE.

Fig 1

Manhattan and QQ plots for the results of meta-analyses adjusting for WBC types. The Manhattan plot shows the chromosomal locations of –log₁₀(P-value) for association at each CpG site; the solid line illustrates a threshold of P-value=2×10⁻⁷ and the dashed line illustrates a threshold of FDR=0.01. The QQ plot shows observed versus expected –log₁₀(P-value) for association at all loci. The gray area illustrates the 95% confidence band.

Fig 2

Partial regression plots of CpG methylation and total IgE for the top four genes in the meta-analysis adjusting for WBC types. The x and y axis respectively stand for the residuals of regressing methylation and IgE against all other covariates, which are adjusted in the multivariable regressions. The solid and hollow circles indicate GALA II and PR-GOAL samples.