4.2 Article

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

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JOURNAL OF ASTHMA
卷 60, 期 10, 页码 1824-1835

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TAYLOR & FRANCIS LTD
DOI: 10.1080/02770903.2023.2193631

关键词

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

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By combining SNPs and mRNA expression, we identified functional genes associated with asthma, including AP2A2 and MUC5AC. Higher expression of MUC5AC and lower expression of MUC5B were correlated with asthma severity. However, SNPs in the chr11p15.5 region were not associated with asthma severity or idiopathic interstitial pneumonias.
ObjectiveGenome-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).MethodsCorrelation 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.ResultsHigher 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).ConclusionsSNPs 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.

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