The Influence of MUC5AC SNPs on expression of MUC5AC and mucus hypersecretion genes during asthma exacerbations
Jackson D, Flynn K, Rosasco M, Gill M, Liu A, Gruchalla R, O G, Pongracic J, Kercsmar C, Hershey GK, Zoratti E, Teach S, Kattan M, Bacharier L, Gergen P, Wheatley L, Presnell S, Togias A, Busse W, and Altman M. The Influence of MUC5AC SNPs on expression of MUC5AC and mucus hypersecretion genes during asthma exacerbations. J Allergy Clin Immunol 2020; 145(2):AB176.
J Allergy Clin Immunol
Rationale: Few genetic studies have specifically defined the functional consequences of genetic variations during respiratory illnesses and asthma exacerbations; we identified genetic variants that impact molecular pathways during asthma exacerbations in children with exacerbation-prone disease. Methods: Serial longitudinal nasal lavage samples were collected from 106 children with exacerbation-prone asthma during three phases: asthma under control, upper respiratory infections, and asthma exacerbations. These samples were used to generate high throughput RNA-sequencing data for both gene expression and single nucleotide polymorphism (SNP) genotype determination. Expression quantitative trait loci (eQTL) analyses were performed by linear mixed-effects modeling and allele specific expression analyses by using a beta-binomial model. Results: 13 local SNPs in the MUC5AC region of chromosome 11 demonstrated significant association with both MUC5ACexpression (fold-changes=1.25-2.0, FDR<0.05) and aggregate expression of a gene module containing MUC5ACand 68 other genes related to mucus hypersecretion and eosinophil activation. These relationships were significant specifically during respiratory illnesses and most pronounced during asthma exacerbations, but were not significant during disease control. TheMUC5ACcoding SNP rs1132440 [synonymous variant R (CGG) àR (CGC)] showed allele specific expression of MUC5ACtranscript levels with the alternate allele (C) showing significantly higher expression than the reference allele in heterozygotic individuals (allelic-fold-change=1.53, FDR<0.05). Conclusions: MUC5AC has pathogenic roles in asthma related to airway hyper-responsiveness and mucus plugging during exacerbations. Our findings demonstrate that genetic polymorphisms in the MUC5AC gene region affect expression of this gene along with a broader molecular module of type 2 inflammation during respiratory illnesses and asthma exacerbations in children.