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 LTC4 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 LTC4 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.