Leukotriene C4 Synthase (LTC4S)
Leukotriene C4 synthase conjugates glutathione with LTA4 to form LTC4, the first cysteinyl leukotriene in the 5-lipoxygenase pathway. The human LTC4 synthase gene (LTC4S) consists of five exons, ranging between 71 and 257 bp, spans 2.51 kb, and has been mapped to chromosome 5q35. A gene promoter polymorphism (A-444C, rs730012) has been previously associated with increased production and expression of LTC4 by blood eosinophils (C allele). Five of the ten published pharmacogenetic studies on the LTC4S -444 A>C polymorphism showed an improved response to LTRAs (FEV1) from patients carrying the C allele, although results were not always statistically significant. The other five published studies could not reproduce these findings. More recently, a study of zileuton responses (FEV1 change over time) in 577 asthma subjects failed to identify a pharmacogenetic effect of the LTC4S-444 polymorphism. However, an alternative LTC4S polymorphism (rs272431, intron 1) was associated with improved responses (mean FEV1 AA = 2.30 l; AC = 3.11 l; p = 0.006). As these results were obtained in different populations and using different end points, the relative contribution of LTC4S polymorphism to LTRA or LTSI therapeutic responses in asthma are still unclear. We therefore suggest that further studies are required in multiple ethnic background populations in order to evaluate these multiple polymorphisms spanning the LTC4S gene.