Priyadarshini Kachroo, PhD
Instructor and Associate Epidemiologist
Recto Kathryn, Kachroo Priyadarshini, Huan Tianxiao, Van Den Berg David, Lee Gha Young, Lee Dong Heon, Gereige Jessica, Yao Chen, Hwang Shih-Jen, Joehanes Roby, Weiss Scott T., O’Connor George, Levy Daniel, DeMeo Dawn L.
Dr. Dawn L. DeMeo and Dr. Daniel Levy
Research Category: Lung Research
Background: Identifying novel epigenetic signatures associated with serum immunoglobulin E (IgE) may improve our understanding of the molecular mechanisms underlying asthma and IgE-related diseases.
Methods and Results: We performed an epigenome-wide association study to identify differential DNA methylation associated with circulating IgE levels from 3471 participants in the Framingham Heart Study (FHS). We validated our results using two independent cohorts: the Childhood Asthma Management Program (CAMP; n=674) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n=787). We identified 490 statistically significant CpGs in FHS; 193 of those replicated in both CAMP and CRA (FDR<0.05). In-silico analysis of the closest gene revealed enrichment in pathways related to transcription factor binding, asthma, and other immune system processes and for histone marks (H3K36me3, H3K4me1 and H3K4me3) from fetal thymus, lung, skin, and blood tissue (FDR <0.01). We further identified 124 cis-expression quantitative trait methylation loci (eQTMs) after analyzing the expression of associated genes (FDR <0.05). Two-sample Mendelian randomization with methylation quantitative trait loci and drug-target analysis revealed CTSB and USP20 as putatively causal regulators of IgE levels (p-value < 7.94E-04) which can be explored as potential therapeutic targets.
Conclusion: Our findings provide multidimensional understanding of inter-relations between DNA methylation, gene expression, and IgE regulation.
Immunoglobulin E (IgE) is a class of antibodies produced by the immune system usually in response to allergen exposures. Integrating environmentally perturbed IgE-associated DNA methylation with associated gene expression may enhance the clinical relevance of the molecular drivers underlying asthma and IgE-related diseases. To date, none of the previously published epigenome-wide association studies (EWAS) of IgE have taken a multifaceted approach and investigated the associated molecular mechanisms in the general population and in people with asthma. We performed an EWAS using 3471 Framingham Heart Study (FHS) participants and validated results using the Childhood Asthma Management Program (CAMP; n=674) and the Genetic Epidemiology of Asthma in Costa Rica Study (CRA; n=787). In this study, we identified significant differential methylation associated with circulating IgE levels in 193 CpG sites (43.9%) at an FDR threshold of 0.05 shared between our discovery and validation cohorts. We further highlight known biomarkers and putatively causal regulators of asthma underlying IgE regulation.