The prevalence of asthma in industrialized nations increased from the 1960s into the 1990s, now affecting ~22 million persons in the United States. The vitamin D hypothesis, which states that vitamin D insufficiency increases the risk and severity of asthma, may partly explain this rise. Vitamin D insufficiency is associated with increased risk of asthma exacerbations in multiple populations, and likely plays a role in host response to respiratory viral infection. We hypothesize that Vitamin D Receptor (VDR) binding is cell specific and influences gene expression in pathways that are relevant to asthma (such as response to viral infections), and that these pathways harbor SNPs that interact with vitamin D levels to influence asthma risk and disease severity. To test this hypothesis, in Aim 1 we will conduct a genome-wide survey of VDR binding in bronchial epithelial and smooth muscle cells treated with varying doses of calcitriol. We will then measure genome-wide gene expression in calcitriol-stimulated bronchial epithelial cells treated with TLR-agonists to simulate viral infecton (Aim 2). Finally, we will integrate the results from Aims 1 and 2 to improve the power of a genome-wide gene- by-vitamin D interaction scan (GWIS) in Puerto Rican children to detect polymorphisms that influence risk of asthma exacerbations (Aim 3). This proposal should help elucidate the role of vitamin D on asthma in general and in children in a high-risk ethnic minority group (Puerto Ricans) in particular.
Vitamin D deficiency and genetic variants in the vitamin D pathway may play an important role in determining asthma severity. This project will characterize the direct and indirect effects of vitamin D on gene expression in airway epithelial and smooth muscle cells. It will then use this information to help identify genetic variants responsible for disease risk and severity.
|Chen, Wei; Brehm, John M; Manichaikul, Ani et al. (2015) A genome-wide association study of chronic obstructive pulmonary disease in Hispanics. Ann Am Thorac Soc 12:340-8|
|Brehm, John M; Man Tse, Sze; Croteau-Chonka, Damien C et al. (2015) A Genome-Wide Association Study of Post-bronchodilator Lung Function in Children with Asthma. Am J Respir Crit Care Med 192:634-7|
|Brehm, John M (2014) Vitamin D and asthma-life after VIDA? Curr Allergy Asthma Rep 14:461|