Differential epigenome-wide DNA methylation patterns in childhood obesity-associated asthma
Authors: Rastogi, Deepa; Suzuki, Masako; Greally, John M.
While DNA methylation plays a role in T-helper (Th) cell maturation, its potential dysregulation in the non-atopic Th1-polarized systemic inflammation observed in obesity-associated asthma is unknown. We studied DNA methylation epigenome-wide in peripheral blood mononuclear cells (PBMCs) from 8 obese asthmatic pre-adolescent children and compared it to methylation in PBMCs from 8 children with asthma alone, obesity alone and healthy controls. Differentially methylated loci implicated certain biologically relevant molecules and pathways. PBMCs from obese asthmatic children had distinctive DNA methylation patterns, with decreased promoter methylation of CCL5, IL2RA and TBX21, genes encoding proteins linked with Th1 polarization, and increased promoter methylation of FCER2, a low-affinity receptor for IgE, and of TGFB1, inhibitor of Th cell activation. T-cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These findings suggest that dysregulated DNA methylation is associated with non-atopic inflammation observed in pediatric obesity-associated asthma.
ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults
CLINICAL AND EXPERIMENTAL ALLERGY
Authors: Vijverberg, S. J. H.; Koster, E. S.; Tavendale, R.; Leusink, M.; Koenderman, L.; Raaijmakers, J. A. M.; Postma, D. S.; Koppelman, G. H.; Turner, S. W.; Mukhopadhyay, S.; Tse, S. M.; Tantisira, K. G.; Hawcutt, D. B.; Francis, B.; Pirmohamed, M.; Pino-Yanes, M.; Eng, C.; Burchard, E. G.; Palmer, C. N. A.; Maitland-van der Zee, A. H.
BackgroundThe clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. MethodsWe performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n=357, age: 4-12years, the Netherlands), BREATHE (n=820, age: 3-22years, UK) and Paediatric Asthma Gene Environment Study (n=391, age: 2-16years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n=172, age: 5-12years, USA), the Genes- environment and Mixture in Latino Americans II- study (n=745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n=391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. ResultsTwo SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR=1.22 (P=0.013) and OR=1.22 (P=0.0017), respectively. Conclusion and clinical relevanceA novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.