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 - 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
SN - 0091-6749
VL - 148
SP - 1505
EP - 1514
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -