MUC5AC and inflammatory mediators associated with respiratory outcomes in the British 1946 birth cohort.

BACKGROUND AND OBJECTIVE: Dysregulation of respiratory mucins, MUC5AC in particular, has been implicated in respiratory disease and MUC5AC expression is up-regulated in response to environmental challenges and inflammatory mediators. The aim of this study was to examine the effect of genetic variation on susceptibility to common respiratory conditions. METHODS: The association of MUC5AC and the closely linked genes MUC2 and MUC5B with respiratory outcomes was tested in the MRC National Survey of Health and Development, a longitudinal birth cohort of men and women born in 1946. Also examined were the functional variants of the genes encoding inflammatory mediators, IL13, IL1B, IL1RN, TNFA and ERBB1, for which there is a likely influence on MUC5AC expression and were explored potential gene-gene interactions with these inflammatory mediators. RESULTS: Statistically significant associations between the 3'ter MUC5AC simple nucleotide polymorphism (SNP) rs1132440 and various non-independent respiratory outcomes (bronchitis, wheeze, asthma, hay fever) were reported while the adjacent loci show slight (but largely non-statistically significant) differences, presumably reflective of linkage disequilibrium (allelic association) across the region. A novel association between bronchitis and a non-synonymous functional ERBB1 SNP, rs2227983 (aka epidermal growth factor receptor:R497K, R521K) is also reported and evidence presented of interaction between MUC5AC and ERBB1 and between MUC5AC and IL1RN with respect to bronchitis. The ERBB1 result suggests a clear mechanism for a biological interaction in which the allelic variants of epidermal growth factor receptor differentially affect mucin expression. CONCLUSIONS: The MUC5AC association and the interactions with inflammatory mediators suggest that genetically determined differences in MUC5AC expression alter susceptibility to respiratory disease.

Cis-acting allelic variation in MUC5B mRNA expression is associated with different promoter haplotypes.

Mucins play a critical role in protecting and clearing the airways of noxious materials. Genetic variation that influences this environmental response is likely to affect respiratory disease susceptibility. It has been reported previously that variation in the promoter of MUC5B, the gene that encodes one of the two major gel-forming mucins (MUC5B) of the mucus of the respiratory tract, is associated with susceptibility to diffuse panbronchiolitis, and that a genetic difference in promoter activity can be detected in vitro. The aim of this study was to determine whether this genetic difference in promoter activity can be detected in vivo. Here, we undertake RNA transcript expression studies, making use of human fetal tissue to explore constitutive differences. We compare in vivo transcript expression levels in heterozygotes and use the Bayesian method, PHASE to associate exonic simple nucleotide polymorphisms (SNPs) with promoter SNPs to generate haplotypes. We successfully show haplotypic differences in MUC5B expression in vivo. This genetic variation should be taken into account in future studies on MUC5B in respiratory disease.