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

Johnson, Lauren, Shah, Imran, Loh, Andrew X., Vinall, Lynne E., Teixeira, Ana S., Rousseau, Karine, Holloway, John W., Hardy, Rebecca and Swallow, Dallas M. (2013) MUC5AC & inflammatory mediators associated with respiratory outcomes in the British 1946 birth cohort. Respirology, 18 (6), 1003-1010. (doi:10.1111/resp.12092). (PMID:23551418)

Abstract

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. Our aim is to examine the effect of genetic variation on susceptibility to common respiratory conditions.

METHODS: We test for association of MUC5AC and the closely linked genes MUC2 and MUC5B with respiratory outcomes in the MRC National Survey of Health and Development (NSHD), a longitudinal birth cohort of men and women born in 1946. We also examine 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 explore potential gene-gene interactions with these inflammatory mediators with respect to respiratory disease.

RESULTS: We report here statistically significant associations between the 3'ter MUC5AC SNP rs1132440 and various non-independent respiratory outcomes (bronchitis, wheeze, asthma, hay fever) 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 EGFR: 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 interaction suggests a clear mechanism for a biological interaction in which the allelic variants of EGFR 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.

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Contributors

Author: John W. Holloway

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