The cysteinyl-leukotrienes (cys-LTs) are proinflammatory mediators that are important in the pathophysiology of asthma. LTC₄ synthase is a key enzyme in the cys-LT biosynthetic pathway, and studies in small populations have suggested that a promoter polymorphism (A_-444C) in the gene might be associated with asthma severity and aspirin intolerance.

We sought to screen the LTC₄ synthase gene for polymorphisms and to determine whether there is an association between these polymorphisms and asthma severity or aspirin sensitivity in a large, well-phenotyped population and to determine whether this polymorphism is functionally relevant.

The coding regions of the LTC₄ synthase gene were screened for polymorphisms and the A_-444C polymorphism was analyzed in a large Australian white adult population of mild (n=282), moderate (n=236), and severe asthmatic subjects (n=86) and nonasthmatic subjects (n=458), as well as in aspirin-intolerant asthmatic subjects (n=67). The functional activity of the promoter polymorphism was investigated by transient transfection of HL-60 cells with a promoter construct.

A new polymorphism was identified in intron 1 of the gene (IVS1-10c>a) but was not associated with asthma. Association studies showed that the A_-444C polymorphism was weakly associated with asthma per se, but there was no association between the C_-444 allele and chronic asthma severity or aspirin intolerance. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity in C_-444 allele frequencies within different clinical subgroups. In vitro functional studies showed no significant differences in transcription efficiency between constructs containing the A_-444 allele or the C_-444 allele.

Our data confirm that, independent of transcriptional activity, the C_-444 allele in the LTC₄ synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance.