Epigenetic marks identify asthma susceptibility in African Americans

Abstract

Despite advances in therapeutics and a better understanding of environmental contributions, ethnic disparities are profound in asthma; asthma prevalence is >2 times higher in African compared to European Americans, and African American children are >3 times more likely to be hospitalized and die from asthma than whites. Epigenetic marks, including DNA methylation, are a key mechanistic component of gene‐environment interactions that affect gene expression, respiratory epithelial dysfunction, and immune cell skewing in asthma. Our group performed pioneering work to identify asthma associated‐DNA methylation changes that affect gene expression in African American inner city children. Our work identified 81 differentially methylated regions (DMRs) in peripheral blood mononuclear cells (PBMCs) associated with allergic asthma. DNA methylation changes in PBMCs are small (median 1.3%; range 0.02%‐3.1%) but consistent with the majority of DMRs hypomethylated in asthma, including important immune genes such as IL‐13, RUNX3, and TIGIT. In the nasal epithelia, we identified much larger (median 9.5%, range: 2.6‐29.5%) methylation changes, both in the form of single CpG methylation (differentially methylated positions[DMPs]) and regions (DMRs). 60% of genes that are differentially expressed in the asthmatic nasal epithelium have significant associations of DNA methylation and gene expression; these include asthma genes (ALOX15, CAPN14, POSTN), genes involved in inflammation and immunity, cell adhesion, extracellular matrix, obesity and autophagy, and epigenetic regulators, among others. Importantly, these results have been replicated in multiple cohorts, including a cohort of Puerto Rican children, another population that shares an unproportional disease burden. We are currently involved in projects that aim to integrate genetic ancestry, DNA methylation, and gene expression data to better understand genetic underpinnings of these DNA methylation changes. Our earlier work also showed that nasal epithelia capture disease activity seen in the lung airway epithelia but that there are many more significant associated DNA methylation changes in the nasal epithelia, suggesting an important role for the environment in influencing these epigenetic changes and the need to understand environmental exposures that are driving these changes. In summary, our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner‐city children provide new targets for understanding the biology of the disease, developing biomarkers of exposure or disease, and potentially identifying novel therapeutic approaches for this disease.