Genetic analyses of chr11p15.5 region identify MUC5AC-MUC5B associated with asthma-related phenotypes
Year: 2023
Type: article
Study design: Observational Study
Abstract: Objective Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) in chr11p15.5 region associated with asthma and idiopathic interstitial pneumonias (IIPs). We sought to identify functional genes for asthma by combining SNPs and mRNA expression in bronchial epithelial cells (BEC) in the Severe Asthma Research Program (SARP).Methods Correlation analyses of mRNA expression of six candidate genes (AP2A2, MUC6, MUC2, MUC5AC, MUC5B, and TOLLIP) and asthma phenotypes were performed in the longitudinal cohort (n = 156) with RNAseq in BEC, and replicated in the cross-sectional cohort (n = 155). eQTL (n = 114) and genetic association analysis of asthma severity (426 severe vs. 531 non-severe asthma) were performed, and compared with previously published GWASs of IIPs and asthma.Results Higher expression of AP2A2 and MUC5AC and lower expression of MUC5B in BEC were correlated with asthma, asthma exacerbations, and T2 biomarkers (P < 0.01). SNPs associated with asthma and IIPs in previous GWASs were eQTL SNPs for MUC5AC, MUC5B, or TOLLIP, however, they were not in strong linkage disequilibrium. The risk alleles for asthma or protective alleles for IIPs were associated with higher expression of MUC5AC and lower expression of MUC5B. rs11603634, rs12788104, and rs28415845 associated with moderate-to-severe asthma or adult onset asthma in previous GWASs were not associated with asthma severity (P > 0.8).Conclusions SNPs associated with asthma in chr11p15.5 region are not associated with asthma severity neither with IIPs. Higher expression of MUC5AC and lower expression of MUC5B are risk for asthma but protective for IIPs.
Source: Journal of Asthma
Authors: Xingnan Li, Huashi Li, Stephanie A. Christenson, Mario Castro, Loren C. Denlinger, Serpil C. Erzurum, John V. Fahy, Benjamin M. Gaston, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, David T Mauger, Wendy C. Moore, Joe Zein, Naftali Kaminski, Sally E. Wenzel, Prescott G. Woodruff, Eugene R. Bleecker, Deborah A. Meyers, for the NHLBI Severe Asthma Research Program (SARP)
Institutions: University of Arizona, University of California, San Francisco, University of Kansas, University of Kansas Medical Center, University of Wisconsin–Madison, Cleveland Clinic, Cleveland Clinic Research, Riley Hospital for Children, Indiana University Indianapolis, Brigham and Women's Hospital, Harvard University, Pennsylvania State University, Wake Forest University Health Sciences, Wake Forest University, Yale University, University of Pittsburgh
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Amgen, Eli Lilly and Company, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Biogen, Patient-Centered Outcomes Research Institute, Teva Pharmaceutical Industries, COPD Foundation, CSL Behring, Regeneron Pharmaceuticals, Vitaflo, Riley Children's Foundation, Veracyte, Glenmark Pharmaceuticals, Shionogi, Sun Pharma, National Institutes of Health, Genentech, Sanofi Genzyme, Propeller Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1044130170, G115506582, G1470284823, G1487269025, G1636177350, G1662581949, Implications and Stability of Clinical and Molecular Phenotypes of Severe Asthma, G1805747755, G1814561639, G1956480145, G196810821, G1979271746, G2071683481, G2488713096, G2630342037, G2824222223, Clinical Coordinating Center for the Severe Asthma Research Program (SARP), General Clinical Research Center, G3224275544, Genome Wide Association for Asthma and Lung Function, G413336477, G4891212004, G4918747893, G5316515788, G5514976981, Exploring the biology of persistent type 2 airway niches in asthma, G5994708509, COUNTER REGULATORY LIPID SIGNALS IN SEVERE ASTHMA, G6147520028, Institutional Clinical and Translational Science Award, G6512242003, G678002062, Severe Asthma from Respiratory Infections, G6994262399, G7221295137, General Clinical Research Center, Washington University Institute of Clinical and Translational Sciences (UL1), G835873496, G8506602026, GENERAL CLINICAL RESEARCH CENTER, University of Wisconsin Institute for Clinical and Translational Research, Mentoring Research in Precision Medicine for Lung Disease, Immune-driven Airway Epithelial Dysfunction in Muco-obstructive Asthma, Yale Clinical and Translational Science Award, G94668252
OpenAlex ID: W4353020735