TY - JOUR
T1 - Inducible expression quantitative trait locus analysis of the MUC5AC gene in asthma in urban populations of children
AU - NIAID Inner City Asthma Consortium
AU - Altman, Matthew C.
AU - Flynn, Kaitlin
AU - Rosasco, Mario G.
AU - Dapas, Matthew
AU - Kattan, Meyer
AU - Lovinsky-Desir, Stephanie
AU - O'Connor, George T.
AU - Gill, Michelle A.
AU - Gruchalla, Rebecca S.
AU - Liu, Andrew H.
AU - Pongracic, Jacqueline A.
AU - Khurana Hershey, Gurjit K.
AU - Zoratti, Edward M.
AU - Teach, Stephen J.
AU - Rastrogi, Deepa
AU - Wood, Robert A.
AU - Bacharier, Leonard B.
AU - LeBeau, Petra
AU - Gergen, Peter J.
AU - Togias, Alkis
AU - Busse, William W.
AU - Presnell, Scott
AU - Gern, James E.
AU - Ober, Carole
AU - Jackson, Daniel J.
N1 - Funding Information:
This work in this study was funded by the National Institute of Allergy and Infectious Diseases through the Inner City Asthma Consortium ( UM1 AI11427 ).
Funding Information:
Disclosure of potential conflict of interest: All authors with the exception of P. Gergen, and A. Togias report grants from National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases/Division of Allergy, Immunology, and Transplantation during the conduct of study. M. Altman reports personal fees for consulting from Regeneron. M. Kattan reports consulting fees from Novartis. S. Lovinsky-Desir reports funding from NIH/National Heart, Lung, and Blood Institute (NHLBI) and the Robert Wood Johnson Foundation. G. O’Connor reports consulting fees from AstraZeneca, and reports a grant from Janssen Pharmaceuticals paid to his employing institution. M. Gill reports consulting fees from the American Academy of Allergy, Asthma, and Immunology and the American Academy of Pediatrics. R. Gruchalla reports employment as a special government employee with the Center for Biologics Evaluation and Research, and consulting fees from the Consulting Massachusetts Medical Society. A. Liu is a consultant for Phadia Thermo Fisher, received nonmonetary research support from Phadia Thermo Fisher and Propeller Health/ResMed, and research funding from Avillion; all funds paid to University of Colorado. J. Pongracic reports provisions of study drug for other asthma studies from GlaxoSmithKline, Boehringer-Ingelheim, and Genentech/Novartis. G. K. Khurana Hershey reports advisory board fees from Hoth Therapeutics. E. Zoratti reports consulting fees from Wayne State University. S. Teach reports support from NIH/NHLBI and EJF Philanthropies and royalties from UpToDate. L. Bacharier reports grant support from the NIH/NHLBI, Sanofi, and Vectura, as well as personal fees from GlaxoSmithKline, Genentech, Novartis, Merck, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Regeneron, Vectura, and Circassia. W. Busse reports grants from NIH/NHLBI, during the conduct of the study; personal fees from Novartis, Regeneron, AstraZeneca, GlaxoSmithKline, Genentech, Elsevier, Med Learning Group, Boston Scientific, Medscape. J. Gern reports grants from NIH, personal fees and stock options from Meissa Vaccines Inc, personal fees from AstraZeneca and Ena Therapeutics and a patent on methods for production of rhinoviruses. C. Ober reports personal fees from the American Academy of Asthma, Allergy, and Immunology. D. Jackson reports grants from NIH/NHLBI and GlaxoSmithKline, personal fees for DSMB from Pfizer and for consulting from Novartis, Sanofi-Regeneron, GlaxoSmithKline, Vifor Pharma and Astra Zeneca. The rest of the authors declare that they have no relevant conflicts of interest.
Publisher Copyright:
© 2021 American Academy of Allergy, Asthma & Immunology
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Asthma
KW - MUC5AC
KW - expression quantitative trait
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U2 - 10.1016/j.jaci.2021.04.035
DO - 10.1016/j.jaci.2021.04.035
M3 - Article
C2 - 34019912
AN - SCOPUS:85108269434
VL - 148
SP - 1505
EP - 1514
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 6
ER -