Asthma affects >300 million people worldwide;maternal asthma is among the most significant risks for the development of asthma in her child, but the mechanisms for this effect are largely unknown. The objectives of this project are to uncover the genetic and epigenetic mechanisms for this risk in well-characterized subjects with asthma who have been evaluated at two time points, approximately 10 years apart. We will combine genetic, genomic, and epigenomic approaches to identify differentially expressed genes, and the genetic and epigenetic mechanisms for their differential expression in airway epithelial cells, PHA-stimulated CD4+ T lymphocytes, and airway smooth muscle cells.
Our specific aims are as follows: (i) Discover SNPs that show interactions with maternal asthma status on asthma risk in the child in a genome-wide association study;(ii) Identify differentially expressed genes between offspring of mothers with and without asthma by comparing genome-wide expression patterns and identify genetic variants that account for inter-individual differences in gene expression (eOTLs);(iii) Elucidate epigenetic mechanisms underlying differential gene expression between offspring of mothers with and without asthma by comparing genome-wide methylation patterns using methylated DNA immunoprecipitation and sequencing (MeDIP-seq) and identify methylation QTLs (meQTLs) that contribute to differences in methylation patterns;and (iv) Characterize differences in small RNA populations (including miRNA) in offspring of mothers with and without asthma by high throughput RNA-sequencing (RNA-seq), map eQTLs that contribute to inter-individual variation in miRNA abundance and targeting, and perform integrated analyses of the data generated in Aims 1-4. To our knowledge, these studies will be the first to use genome-wide approaches to elucidate mechanisms underlying the increased risk for asthma in children of mothers with asthma. Using 4 complimentary approaches that integrate genome-wide genetic, genomic, and epigenomic studies in asthma-relevant, primary cells from subjects with asthma should reveal novel genes, regulatory pathways and networks, and mechanisms for asthma pathogenesis.
Maternal asthma is among the most significant risk factors for childhood asthma, but little is known about the mechanisms for this risk. We will use four complementary approaches to elucidate the mechanisms by integrating genome-wide genetic, genomic, and epigenomic studies in asthma-relevant, primary cells from subjects with asthma. These studies should reveal novel genes, regulatory pathways and networks, and mechanisms for asthma pathogenesis.
|Myers, Rachel A; Scott, Nicole M; Gauderman, W James et al. (2014) Genome-wide interaction studies reveal sex-specific asthma risk alleles. Hum Mol Genet 23:5251-9|
|Campbell, Catarina D; Mohajeri, Kiana; Malig, Maika et al. (2014) Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma. PLoS One 9:e104396|
|Dowell, Maria L; Lavoie, Tera L; Solway, Julian et al. (2014) Airway smooth muscle: a potential target for asthma therapy. Curr Opin Pulm Med 20:66-72|
|Chen, Bohao; Moore, Tamson V; Li, Zhenping et al. (2014) Gata5 deficiency causes airway constrictor hyperresponsiveness in mice. Am J Respir Cell Mol Biol 50:787-95|
|White, Steven R; Floreth, Timothy; Liao, Chuanhong et al. (2014) Association of soluble HLA-G with acute rejection episodes and early development of bronchiolitis obliterans in lung transplantation. PLoS One 9:e103643|
|Nicodemus-Johnson, Jessie; Laxman, Bharathi; Stern, Randi K et al. (2013) Maternal asthma and microRNA regulation of soluble HLA-G in the airway. J Allergy Clin Immunol 131:1496-503|
|Doeing, Diana C; Solway, Julian (2013) Airway smooth muscle in the pathophysiology and treatment of asthma. J Appl Physiol 114:834-43|