Publications (2)7.48 Total impact
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Article: MUC5AC & inflammatory mediators associated with respiratory outcomes in the British 1946 birth cohort.
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ABSTRACT: BACKGROUNDAND 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 mediatorssuggest that genetically determined differences in MUC5AC expression alter susceptibility to respiratory disease.Respirology 04/2013; · 2.42 Impact Factor -
Article: Hypervariability of the membrane-associated mucin and cancer marker MUC1.
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ABSTRACT: The highly heterogeneous epithelial mucins show considerable inter-individual variability attributable to allelic variations in their tandem repeat (TR) peptide domains. Most mucins are known to show variations in repeat number but variation in the sequence of the individual TRs is not as well characterised. Here, we have studied variation in the immunodominant PDTR motif in the TR domain of the membrane-associated "cancer" mucin MUC1 by using the Minisatellite Variant Repeat-Polymerase chain reaction (MVR-PCR) technique. We have fully or partially mapped two nucleotide changes that encode two amino-acid changes, PDTR to PESR, across the arrays of 149 alleles. A total of 103 different maps was obtained when these changes alone were considered and additional variations were also observed. Most maps showed blocks of PDTR repeats interspersed with PESR repeats, although these were possibly more irregular in the longer alleles that also tended to have more PESR repeats. This variability has potential functional consequences and possible implications for some individuals with respect to the efficacy of immune targetting and immune therapy.Human Genetics 12/2003; 113(6):473-9. · 5.07 Impact Factor
