Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma

J Allergy Clin Immunol. 2004 May;113(5):889-95. doi: 10.1016/j.jaci.2004.02.008.


Background: The cysteinyl-leukotrienes (cys-LTs) are proinflammatory mediators that are important in the pathophysiology of asthma. LTC(4) synthase is a key enzyme in the cys-LT biosynthetic pathway, and studies in small populations have suggested that a promoter polymorphism (A(-444)C) in the gene might be associated with asthma severity and aspirin intolerance.

Objective: We sought to screen the LTC(4) 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.

Methods: The coding regions of the LTC(4) synthase gene were screened for polymorphisms and the A(-444)C 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.

Results: 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(-444)C 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.

Conclusions: Our data confirm that, independent of transcriptional activity, the C(-444) allele in the LTC(4) synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Aspirin
  • Asthma / enzymology*
  • Asthma / genetics*
  • Australia
  • Case-Control Studies
  • Drug Tolerance / genetics
  • Female
  • Glutathione Transferase / genetics*
  • Glutathione Transferase / metabolism
  • HL-60 Cells
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Genetic*
  • Polymorphism, Restriction Fragment Length
  • Polymorphism, Single-Stranded Conformational
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transfection


  • Recombinant Proteins
  • Glutathione Transferase
  • leukotriene-C4 synthase
  • Aspirin