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.
| Stein, Michelle M; Thompson, Emma E; Schoettler, Nathan et al. (2018) A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. J Allergy Clin Immunol 142:749-764.e3 |
| Hrusch, C L; Manns, S T; Bryazka, D et al. (2018) ICOS protects against mortality from acute lung injury through activation of IL-5+ ILC2s. Mucosal Immunol 11:61-70 |
| Ober, Carole; Sperling, Anne I; von Mutius, Erika et al. (2017) Immune development and environment: lessons from Amish and Hutterite children. Curr Opin Immunol 48:51-60 |
| White, Steven R; Nicodemus-Johnson, Jessie; Laxman, Bharathi et al. (2017) Elevated levels of soluble humanleukocyte antigen-G in the airways are a marker for a low-inflammatory endotype of asthma. J Allergy Clin Immunol 140:857-860 |
| Press, Valerie G; Kelly, Colleen A; Kim, John J et al. (2017) Virtual Teach-To-Goal™ Adaptive Learning of Inhaler Technique for Inpatients with Asthma or COPD. J Allergy Clin Immunol Pract 5:1032-1039.e1 |
| Krishack, Paulette A; Wang, Kanix; Rzhetsky, Andrey et al. (2017) Preexisting Type 2 Immune Activation Protects against the Development of Sepsis. Am J Respir Cell Mol Biol 57:628-630 |
| Narayanamurthy, Vaishnavi; Sweetnam, John M; Denner, Darcy R et al. (2017) The metabolic footprint of the airway bacterial community in cystic fibrosis. Microbiome 5:67 |
| Johnston, Henry Richard; Hu, Yi-Juan; Gao, Jingjing et al. (2017) Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome. Sci Rep 7:46398 |
| Igartua, Catherine; Davenport, Emily R; Gilad, Yoav et al. (2017) Host genetic variation in mucosal immunity pathways influences the upper airway microbiome. Microbiome 5:16 |
| Ober, Carole (2016) Asthma Genetics in the Post-GWAS Era. Ann Am Thorac Soc 13 Suppl 1:S85-90 |
Showing the most recent 10 out of 42 publications
