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

Abstract

Background Total immunoglobulin E (IgE) is a therapeutic target in allergic diseases. DNA methylation in white blood cells (WBCs) was associated with total IgE in an epigenome-wide association study (EWAS) of Caucasians. Whether DNA methylation of eosinophils explains those findings is insufficiently understood. Methods We tested for association between genome-wide DNA methylation in WBCs and total IgE in two 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, n = 573). Whole-genome methylation of DNA from WBCs was measured using the Illumina Infinium HumanMethylation450 BeadChip. Total IgE was measured using the UniCAP 100 system. In PR-GOAL, WBC types (i.e. neutrophils, eosinophils, basophils, lymphocytes, and monocytes) in peripheral blood were measured using Coulter-Counter techniques. In GALA II, WBC types were imputed. Multivariable linear regression was used for the analysis of DNA methylation and total IgE, which was first conducted separately for each cohort, and then combining results from the two cohorts in a meta-analysis. Results CpG sites in multiple genes, including novel findings and results previously reported in Caucasians, were significantly associated with total IgE. However, adjustment for WBC types resulted in markedly fewer significant sites. Top findings from this adjusted meta-analysis were in genes ZFPM1 (P=1.5×10−12), ACOT7 (P=2.5×10−11), and MND1 (P=1.4×10−9). Conclusions In an EWAS adjusted for WBC types (including eosinophils), methylation changes in genes enriched in pathways relevant to asthma and immune responses were associated with total IgE among Hispanic children.

Epigenome-wide association study of asthma and wheeze in childhood and adolescence

“…In addition, our cell counts are estimated from the methylation data using a reference dataset instead of being directly sorted and counted in the original blood samples. Whereas the method has been previously validated [76] and previous EWAS analyses have found strong correlations between estimated and cell sorted measures [22], it may not perform well in predicting proportions of rarer cell types in the blood, such as eosinophils, as they may be subject to less favourable signalto-noise ratios than high abundance cell types. However, we attempted to counter the potentially poor estimation of cell counts by using surrogate variables in our EWAS analysis, a reference-free method of adjusting for unknown confounding factors.…”

“…A recent EWAS of IgE in Hispanic children [22] reported associations with DNA methylation in CpGs annotated to the ZFPM1 (cg04983687, cg08940169) and ACOT7 (cg09249800, cg21220721, cg11699125) genes. We observe similar strong associations with CpG sites annotated to the same genes in the unadjusted EWAS of current asthma at 7.5 years (Additional file 2: Tables E1 and E2).…”

“…Additionally, we have used exclusively methylation-estimated cell counts to adjust for cell mixture as opposed to cell sorted estimates of the previous study, leading to potentially imprecise adjustments in our own analyses. In a sensitivity analysis, we generated estimated cell counts using the Houseman algorithm [41] and the 200 reference CpGs supplied in the supplementary material of the previous study [22]. Correlations between the estimated cell counts using the estimated reference CpGs and our own Houseman-derived estimates were relatively low.…”

Insights from deconvolution of cell subtype proportions enhance the interpretation of functional genomic data

“…We conclude that, while it should not be surprising that cell subtype effects need to be taken into account in the interpretation of functional genomics studies, it is probably worth paying more attention to the characterization of the variability of cell subtypes as an insight into the phenotype being tested, rather than discarding the information as merely confounding 1,[45][46][47] . Phenotypes may indeed result from cellular reprogramming, but it is highly plausible that the polycreodism model of altered cell repertoires in a tissue is another potentially very powerful mechanism for mediation of phenotypic changes.…”

Epigenome-wide association study of asthma and wheeze in childhood and adolescence

“…Associations of wheeze with DNA methylation may be expected to capture a wider variety of biological processes that underlie respiratory conditions. Previous studies have reported an association between peripheral blood DNA methylation and IgE (21,22) , an important mediator of atopic or inflammatory diseases such as asthma. However, whether these associations are also present for the asthma phenotype has not been assessed.…”