Date of Award

12-14-2015

Document Type

Open Access Dissertation

Department

Epidemiology and Biostatistics

First Advisor

Melinda Forthofer

Abstract

Asthma, a chronic respiratory condition, is common worldwide with no cure and limited effective prevention strategies. It is well recognized that asthma has a multifaceted etiology, though many of the underlying mechanisms involved in asthma development, persistence and remission are still convoluted. Epigenetic mechanisms, such as DNA methylation, regulate gene-expression but are not related to changes in the actual DNA sequence. Recently, differential patterns of DNA methylation within many genes have been associated with asthma, particularly within genes involved in the differentiation of pro-inflammatory T-helper 2 (Th2) cells. DNA methylation patterns within less known biologic pathways undoubtedly are involved in asthma pathogenesis as well. The purpose of this dissertation was three-fold. First, we explored whether genetic and epigenetic variations within Th2-genes differed among persons with different phenotypic presentations of wheeze illnesses. Second, we conducted an epigenome-wide association study (EWAS) to identify novel DNA methylation loci associated with asthma. Last, we conducted a follow-up study of our top EWAS findings, to investigate whether the expression of the associated genes were predictive of infant wheeze. We found that DNA-M within GATA3 and IL4 varied based on different wheeze-illness phenotypes, suggesting that Th2-genes are under differential epigenetic regulation for different presentations of asthma. We also identified nine novel DNA methylation loci (cg25578728 in CHD7, cg16658191 in HK1, cg00100703 in UNC45B, cg07948085 [intergenic], cg04359558 in LITAF, cg20417424 in ST6GALNAC5, cg19974715 [intergenic], cg01046943 in NUP210 and cg14727512 in DGCR14) associated with asthma at age 18. For two of those genes (HK1 and LITAF), expression levels in cord blood were predictive of infant wheeze. Interestingly, the observed methylation and expression patterns of HK1 and LITAF could be consistent with increased resistance to apoptotic signaling. Apoptotic-resistance among pro-inflammatory cells can increase the duration of an inflammatory response and is affiliated with asthmatic pathophysiology. Thus we may have identified under-studied genes and their epigenetic regulation, which could play important roles in asthma pathophysiology. These genes may offer new insights into the etiology of asthma, be investigated as potential targets for therapy, or be considered for inclusion in algorithms used to predict early-life wheeze and later-life asthma.

Rights

© 2015, Todd M. Everson

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