DNA methylation and childhood asthma in the inner city

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DNA methylation and childhood asthma in the inner city Ivana V. Yang, PhD, Brent S. Pedersen, PhD, Andrew Liu, MD, George T. O'Connor, MD, Stephen J. Teach, MD, MPH, Meyer Kattan, MD, Rana Tawil Misiak, MD, Rebecca Gruchalla, MD, Suzanne F. Steinbach, MD, Stanley J. Szefler, MD, Michelle A. Gill, MD, PhD, Agustin Calatroni, MA, MS, Gloria David, PhD, MHSc, Corinne E. Hennessy, BS, Elizabeth J. Davidson, BA, Weiming Zhang, PhD, Peter Gergen, MD, MPH, Alkis Togias, MD, William W. Busse, MD, David A. Schwartz, MD Journal of Allergy and Clinical Immunology Volume 136, Issue 1, Pages 69-80 (July 2015) DOI: 10.1016/j.jaci.2015.01.025 Copyright © 2015 Terms and Conditions

Fig 1 DMRs are associated with asthma after controlling for age, sex, race, technical variables, and batch effects. A, Manhattan plot of adjusted P values for disease status (asthma/control) from the linear model. Each dot represents a P value for a probe on the Illumina 450k array that has been adjusted by the significance of neighboring probes within 300 bases according to their correlation. Probes within statistically significant DMRs are identified by a darker and slightly larger symbol after adjustment for genome-wide comparisons. B, A representative transcriptional network of genes with associated DMRs from Ingenuity Pathway Analysis. Network analysis was performed with only direct interactions (solid lines) and networks with a score of greater than 20. Genes are intensity colored red (hypermethylated) or green (hypomethylated). Horizontal ellipse, Transcriptional regulator; square, cytokine; double circle, group/complex; triangle, phosphatase; vertical ellipse, transmembrane receptor; rectangle, ion channel. Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions

Fig 2 Differentially methylated marks are associated with higher total serum IgE concentrations (A) and percent predicted FEV1 (B) after controlling for age, sex, race, technical variables, and batch effects among the asthmatic patients. Manhattan plots were constructed in the same fashion as in Fig 1, A. Probes within statistically significant DMRs are identified by a darker and slightly larger symbol after adjustment for genome-wide comparisons. Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions

Fig 3 Expression changes in genes within 3 kb of the nearest DMR associated with asthma in the entire study population (A), IgE levels among asthmatic patients (B), and genome-wide methylation expression in asthmatic patients (C). Fig 3, A, x-axis, The methylation difference is represented by the mean percentage methylation difference in asthmatic patients compared with control subjects. Fig 3, A, y-axis, The expression difference is represented by the mean fold change in asthmatic patients compared with control subjects (on the log base 2 scale). Fig 3, B, The percentage methylation difference on the x-axis is represented by the mean correlation coefficient between IgE and methylation in asthmatic patients. The y-axis is represented by the slope of the IgE covariate in the linear model for expression in asthmatic patients. Blue symbols represent hypomethylated genes associated with increased gene expression, as well as some hypermethylated genes associated with decreased gene expression. Red symbols represent methylation changes that were not associated with expected gene expression differences. Upward triangles indicate DMR location upstream of the gene, circles represent DMRs in the gene body, and downward triangles refer to DMRs downstream of the gene. In Fig 3, C, the t statistic for expression change of all genes in the genome in asthmatic patients compared with control subjects from PBMCs is plotted against the t statistic for methylation changes in these genes (single CpG within the 3-kb promoter). Red dots represent the 207 genes with posterior probability from the joint model of methylation and expression of greater than 0.95 (corresponding to q < 0.05), a methylation t statistic of less than −1.5, and an expression t statistic of greater than 1.5 (see Table E10, A). Additionally, 82 genes have posterior probability of greater than 0.95, a methylation t statistic of less than −1.5, and an expression t statistic of less than −1.5 (lower left quadrant, see Table E10, B). No significant expression/methylation changes were identified in the right 2 quadrants on this plot. Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2015 136, 69-80DOI: (10.1016/j.jaci.2015.01.025) Copyright © 2015 Terms and Conditions