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.
Sayers
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Human Genetics Division, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton S016 6YD, UK. Dr_Ian_Sayers@hotmail.com
Sampson
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Holgate
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D000328:Adult; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects*
D003907:Dexamethasone; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase