title: Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene.
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.
authors.affiliation: Human Genetics Division, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton S016 6YD, UK. Dr_Ian_Sayers@hotmail.com
authors.forename: I
authors.initials: I
authors.lastname: Sayers
authors.forename: A P
authors.initials: AP
authors.lastname: Sampson
authors.forename: S
authors.initials: S
authors.lastname: Ye
authors.forename: S T
authors.initials: ST
authors.lastname: Holgate
mesh_terms: 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*
chemical_list: D003907:Dexamethasone; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase