Matthew C Altman1, Kaitlin Flynn2, Mario G Rosasco2, Matthew Dapas3, Meyer Kattan4, Stephanie Lovinsky-Desir4, George T O'Connor5, Michelle A Gill6, Rebecca S Gruchalla6, Andrew H Liu7, Jacqueline A Pongracic8, Gurjit K Khurana Hershey9, Edward M Zoratti10, Stephen J Teach11, Deepa Rastrogi11, Robert A Wood12, Leonard B Bacharier13, Petra LeBeau14, Peter J Gergen15, Alkis Togias15, William W Busse16, Scott Presnell2, James E Gern16, Carole Ober3, Daniel J Jackson16. 1. Department of Medicine, University of Washington, Seattle, Wash; Benaroya Research Institute, Seattle, Wash. Electronic address: maltman@benaroyaresearch.org. 2. Benaroya Research Institute, Seattle, Wash. 3. Department of Human Genetics, University of Chicago, Chicago, Ill. 4. Columbia University, New York, NY. 5. Boston University School of Medicine, Boston, Mass. 6. University of Texas Southwestern Medical Center, Dallas, Tex. 7. Children's Hospital Colorado University of Colorado School of Medicine, Aurora, Colo. 8. Ann Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill. 9. Cincinnati Children's Hospital, Cincinnati, Ohio. 10. Henry Ford Health System, Detroit, Mich. 11. Children's National Hospital, Washington, DC. 12. Department of Pediatrics, Johns Hopkins University Medical Center, Baltimore, Md. 13. Washington University, St Louis, Mo. 14. Rho Inc, Chapel Hill, NC. 15. National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bethesda, Md. 16. University of Wisconsin School of Medicine and Public Health, Madison, Wis.
Abstract
BACKGROUND: Mucus plugging can worsen asthma control, lead to reduced lung function and fatal exacerbations. MUC5AC is the secretory mucin implicated in mucus plugging, and MUC5AC gene expression has been associated with development of airway obstruction and asthma exacerbations in urban children with asthma. However, the genetic determinants of MUC5AC expression are not established. OBJECTIVES: This study sought to assess single-nucleotide polymorphisms (SNPs) that influence MUC5AC expression and relate to pulmonary functions in childhood asthma. METHODS: This study used RNA-sequencing data from upper airway samples and performed cis-expression quantitative trait loci (eQTL) and allele-specific expression analyses in 2 cohorts of predominantly Black and Hispanic urban children, a high asthma-risk birth cohort, and an exacerbation-prone asthma cohort. Inducible MUC5AC eQTLs were further investigated during incipient asthma exacerbations. Significant eQTLs SNPs were tested for associations with lung function measurements and their functional consequences were investigated in DNA regulatory databases. RESULTS: Two independent groups of SNPs in the MUC5AC gene that were significantly associated with MUC5AC expression were identified. Moreover, these SNPs showed stronger eQTL associations with MUC5AC expression during asthma exacerbations, which is consistent with inducible expression. SNPs in 1 group also showed significant association with decreased pulmonary functions. These SNPs included multiple EGR1 transcription factor binding sites, suggesting a mechanism of effect. CONCLUSIONS: These findings demonstrate the applicability of organ-specific RNA-sequencing data to determine genetic factors contributing to a key disease pathway. Specifically, they suggest important genetic variations that may underlie propensity to mucus plugging in asthma and could be important in targeted asthma phenotyping and disease management strategies.
BACKGROUND: Mucus plugging can worsen asthma control, lead to reduced lung function and fatal exacerbations. MUC5AC is the secretory mucin implicated in mucus plugging, and MUC5AC gene expression has been associated with development of airway obstruction and asthma exacerbations in urban children with asthma. However, the genetic determinants of MUC5AC expression are not established. OBJECTIVES: This study sought to assess single-nucleotide polymorphisms (SNPs) that influence MUC5AC expression and relate to pulmonary functions in childhood asthma. METHODS: This study used RNA-sequencing data from upper airway samples and performed cis-expression quantitative trait loci (eQTL) and allele-specific expression analyses in 2 cohorts of predominantly Black and Hispanic urban children, a high asthma-risk birth cohort, and an exacerbation-prone asthma cohort. Inducible MUC5AC eQTLs were further investigated during incipient asthma exacerbations. Significant eQTLs SNPs were tested for associations with lung function measurements and their functional consequences were investigated in DNA regulatory databases. RESULTS: Two independent groups of SNPs in the MUC5AC gene that were significantly associated with MUC5AC expression were identified. Moreover, these SNPs showed stronger eQTL associations with MUC5AC expression during asthma exacerbations, which is consistent with inducible expression. SNPs in 1 group also showed significant association with decreased pulmonary functions. These SNPs included multiple EGR1 transcription factor binding sites, suggesting a mechanism of effect. CONCLUSIONS: These findings demonstrate the applicability of organ-specific RNA-sequencing data to determine genetic factors contributing to a key disease pathway. Specifically, they suggest important genetic variations that may underlie propensity to mucus plugging in asthma and could be important in targeted asthma phenotyping and disease management strategies.
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