The objective of this project is to determine how genetic variability in genes along the nicotine metabolism and oxidative stress pathways contribute to ETS biomarker misclassification and impact the development of childhood respiratory disorders and asthma, with respect to ETS exposures. This work will identify subjects that are genetically susceptible to the harmful effects of secondhand smoke exposures with respect to asthma as well as provide new insights for personalized therapies. This research is funded by the NIEHS.  

 The airways are lined by ciliated epithelial cells that provide the first line of defense to pollutants, such as secondhand smoke, by clearing mucus. Our division has previously shown that RNA expression in cilia-related genes is down-regulated during asthma exacerbation in children. In adults, cilia length and cilia-related gene expression are reduced in smokers, suggesting smoke damages cilia, affects cilia growth, and that smoke plays a significant role in the pathogenesis of asthma. The objective of this project is to is to elucidate the relationships between secondhand smoke exposures, asthma severity and cilia-related gene expression in children, and determine how variation in these genes modifies these associations. These findings will fuel mechanistic studies and identify unique targets for personalized therapies and interventions aimed at the epithelial surface. This research is funded by the University of Cincinnati CCTST Clinical Research Feasibility Fund. 

Secondhand smoke exposures may predispose children to asthma by inducing bronchial hyper-responsiveness, decreasing lung function and altering lung development. The implementation of smoking bans has reduced smoke exposures, asthma-related ED visits and asthma symptoms and exacerbation in adults and children overall, but race-specific investigations are lacking. Compared to Caucasians, African-American children have a higher asthma prevalence and increased hospitalization due to asthma and asthma-related mortality rates, as well as consistently higher cotinine levels. African-Americans also suffer disparities in the effects of smoke-free legislation. The goals of this study are to determine the age(s) that smoke exposures have the greatest impact on childhood asthma development and evaluate the differences in the effectiveness of smoke-free legislation on respiratory symptoms and asthma-related ED visits between Caucasian and African-American children. These studies will provide age-specific targets for secondhand smoke prevention and a better fundamental understanding of the origination of asthma, as well as identify racial disparities in smoke-free legislation efficacy in asthma morbidity. Since public policies prohibiting smoking may not address the needs of the pediatric African-American population, future studies may need to implement community preventions or direct interventions into the home.

 In collaboration with Dr. Hershey’s NIAID funded Asthma and Allergic Diseases Cooperative Research Centers U19 grant, we developed two custom SNP arrays to evaluate the role of genes related to the epithelium, immunity, the skin barrier, inflammation and oxidative stress in pediatric asthma, atopic dermatitis and allergic rhinitis. We then genotyped over 1500 cases and controls to assess the effects of skin-barrier related candidate genes and asthma development. We also utilized mechanistic and biologic plausibility of epistasis to investigate interactions between the candidate genes. We were able to replicate our findings of genetic interaction in asthma in a population where neither gene was independently associated with the disease, highlighting the importance of using biology to evaluate epistasis in genetic association studies and the value of looking at functionally related genes to identify those with clinical relevance. Our future projects will use these methods to examine epistasis in these and other functionally related genes and include additional allergic diseases as well as environmental exposures to evaluate gene-environment interactions.  

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Reprinted from Fig. 3 published in J Allergy Clin Immunol 2014 May 13. Biagini Myers JM, Martin LJ, Butsch Kovacic M, Mersha TB, He H, Pilipenko V, Lindsey MA, Ericksen MB, Bernstein DI, LeMasters GK, Lockey JE, Khurana Hershey GK. Epistasis between serine protease inhibitor Kazal-type 5 (SPINK5) and thymic stromal lymphopoietin (TSLP) genes contributes to childhood asthma. Copyright © 2014, Biagini Myers et al. with permissions from Elsevier.