Leukotriene C4 Synthase: A Candidate Gene for the Aspirin-Intolerant Asthmatic Phenotype

Abstract

The features of the allergic inflammation underlying asthma occur as a consequence of mediators such as the cysteinyl LTs. The generation of the cysteinyl LTs is carefully regulated and dependent on the 5-LO/LTC4S pathway, of which LTC4S is the pivotal and only committed enzyme involved. Although LTC4S is related to other proteins involved in eicosanoid metabolism, it is clearly a distinct member within a novel gene family, and site directed mutagenic studies of LTC4S have identified two critical residues necessary for its specific conjugation of LTA4 to GSH. This observation, as well as the limited cellular distribution, and chromosomal localization are consistent with LTC4S as a candidate gene for asthma, having diverged from its other gene family members. More specifically, profound overexpression of LTC4S in aspirin-induced asthma seems to be a principal determinant of the respiratory reactions to aspirin, and a single-nucleotide polymorphism in the 5' regulatory region associates significantly with the aspirin-intolerant phenotype in Polish patients. This data strongly support LTC4S as a candidate gene in this phenotype of asthma, and further characterization of LTC4S in terms of enzymatic function and gene regulation will likely contribute to the understanding of the gene as one potentially responsible for the allergic inflammation underlying aspirin-intolerance. Additionally, discovery of additional polymorphism within this gene may lead to identification of susceptibility to adverse aspirin reactions, and inhibition of this enzyme may represent a therapeutic target for compounds useful in the treatment of asthma and allergic diseases.