Genetic analyses of chr11p15.5 region identify MUC5AC-MUC5B associated with asthma-related phenotypes

for the NHLBI Severe Asthma Research Program (SARP)

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1824-1835
Number of pages12
JournalJournal of Asthma
Volume60
Issue number10
DOIs
StatePublished - 2023

Keywords

  • Asthma susceptibility
  • MUC5AC
  • MUC5B
  • asthma severity
  • eQTL
  • gene expression
  • genetic association

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Immunology and Allergy
  • Pulmonary and Respiratory Medicine

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