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

MUC5AC & inflammatory mediators associated with respiratory outcomes in the British 1946 birth cohort
MUC5AC & 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. 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.
1323-7799
1003-1010
Johnson, Lauren
9faa9932-b329-484e-be24-5ff3077355e3
Shah, Imran
e1101067-3c0e-4b20-b50f-dd9e9fd2cb78
Loh, Andrew X.
d65bb431-21a8-4eca-904d-148719198470
Vinall, Lynne E.
a604c900-fd3e-43de-9e80-7fe699cecbb1
Teixeira, Ana S.
a94400eb-76c6-4683-aa78-539df4682076
Rousseau, Karine
0cee561a-9d0d-4e0c-ab28-f7ddb433b5aa
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Hardy, Rebecca
99fecbaf-fc92-4354-aa02-cb904dd2bd32
Swallow, Dallas M.
df1e5578-2419-4ef6-a9ea-bbe9998a15fe
Johnson, Lauren
9faa9932-b329-484e-be24-5ff3077355e3
Shah, Imran
e1101067-3c0e-4b20-b50f-dd9e9fd2cb78
Loh, Andrew X.
d65bb431-21a8-4eca-904d-148719198470
Vinall, Lynne E.
a604c900-fd3e-43de-9e80-7fe699cecbb1
Teixeira, Ana S.
a94400eb-76c6-4683-aa78-539df4682076
Rousseau, Karine
0cee561a-9d0d-4e0c-ab28-f7ddb433b5aa
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Hardy, Rebecca
99fecbaf-fc92-4354-aa02-cb904dd2bd32
Swallow, Dallas M.
df1e5578-2419-4ef6-a9ea-bbe9998a15fe

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)

Record type: Article

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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More information

e-pub ahead of print date: 2 April 2013
Published date: August 2013
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 350827
URI: http://eprints.soton.ac.uk/id/eprint/350827
ISSN: 1323-7799
PURE UUID: d1bafe57-19ac-46c6-b441-4ec72fb2c47f
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 08 Apr 2013 14:13
Last modified: 09 Jan 2022 02:54

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Contributors

Author: Lauren Johnson
Author: Imran Shah
Author: Andrew X. Loh
Author: Lynne E. Vinall
Author: Ana S. Teixeira
Author: Karine Rousseau
Author: Rebecca Hardy
Author: Dallas M. Swallow

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