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Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene

Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene
Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene
The molecular mechanisms of corticosteroid action in asthma are gradually being elucidated. The LTC4S gene encodes for LTC(4) synthase, the terminal enzyme in the generation of cysteinyl-leukotrienes (cys-LTs), which are key mediators in the pathogenesis of asthma. We have identified a novel promoter polymorphism in LTC4S at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. We hypothesised that the LTC4S gene promoter may be a potential site of regulation by corticosteroids and that genetic polymorphism may determine their effects at this locus. Using in vitro transfection of promoter-reporter constructs, dexamethasone was shown to increase transcription of LTC4S by more than 50% for the -1072G/-444A, A-C and G-C haplotype constructs (P&<0.02), but to have no effect on the A-A haplotype (P=0.27). These data identify an interesting phenomenon that requires validation in a human study examining ex vivo production of LTC(4) in cells from genotyped asthmatic and nonasthmatic subjects. The 9% of the Caucasian asthmatic population with the A-A haplotype may have genetically predetermined lower cys-LT levels in the presence of corticosteroids compared to other patients. These findings have potential implications in the evaluation of combined corticosteroid and antileukotriene therapy in asthma.
asthma, LTC4S, promoter polymorphism, corticosteroids, transcription
1018-4813
619-622
Sayers, I.
230e01df-0685-438a-9173-df1aead72390
Sampson, A.P.
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
Ye, S.
73027825-861c-4bca-8ce6-67a325fa2d2c
Holgate, S.T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Sayers, I.
230e01df-0685-438a-9173-df1aead72390
Sampson, A.P.
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
Ye, S.
73027825-861c-4bca-8ce6-67a325fa2d2c
Holgate, S.T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc

Sayers, I., Sampson, A.P., Ye, S. and Holgate, S.T. (2003) Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene. European Journal of Human Genetics, 11 (8), 619-622. (doi:10.1038/sj.ejhg.5201015).

Record type: Article

Abstract

The molecular mechanisms of corticosteroid action in asthma are gradually being elucidated. The LTC4S gene encodes for LTC(4) synthase, the terminal enzyme in the generation of cysteinyl-leukotrienes (cys-LTs), which are key mediators in the pathogenesis of asthma. We have identified a novel promoter polymorphism in LTC4S at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. We hypothesised that the LTC4S gene promoter may be a potential site of regulation by corticosteroids and that genetic polymorphism may determine their effects at this locus. Using in vitro transfection of promoter-reporter constructs, dexamethasone was shown to increase transcription of LTC4S by more than 50% for the -1072G/-444A, A-C and G-C haplotype constructs (P&<0.02), but to have no effect on the A-A haplotype (P=0.27). These data identify an interesting phenomenon that requires validation in a human study examining ex vivo production of LTC(4) in cells from genotyped asthmatic and nonasthmatic subjects. The 9% of the Caucasian asthmatic population with the A-A haplotype may have genetically predetermined lower cys-LT levels in the presence of corticosteroids compared to other patients. These findings have potential implications in the evaluation of combined corticosteroid and antileukotriene therapy in asthma.

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More information

Published date: August 2003
Keywords: asthma, LTC4S, promoter polymorphism, corticosteroids, transcription

Identifiers

Local EPrints ID: 27414
URI: http://eprints.soton.ac.uk/id/eprint/27414
ISSN: 1018-4813
PURE UUID: d02c6411-1620-4185-9ead-d9833a9d8321
ORCID for A.P. Sampson: ORCID iD orcid.org/0009-0008-9653-8935

Catalogue record

Date deposited: 27 Apr 2006
Last modified: 16 Mar 2024 02:51

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Contributors

Author: I. Sayers
Author: A.P. Sampson ORCID iD
Author: S. Ye
Author: S.T. Holgate

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