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

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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.

Document Type: Research Article

DOI: http://dx.doi.org/10.2500/108854199778251825

Publication date: November 1, 1999

More about this publication?
  • Allergy and Asthma Proceedings is a peer reviewed publication dedicated to distributing timely scientific research regarding advancements in the knowledge and practice of allergy, asthma and immunology. Its primary readership consists of allergists and pulmonologists.

    The goal of the Proceedings is to publish articles with a predominantly clinical focus which directly impact quality of care for patients with allergic disease and asthma.

    Featured topics include asthma, rhinitis, sinusitis, food allergies, allergic skin diseases, diagnostic techniques, allergens, and treatment modalities. Published material includes peer-reviewed original research, clinical trials and review articles.

    Articles marked "F" offer free full text for personal noncommercial use only.

    The journal is indexed in Thomson Reuters Web of Science and Science Citation Index Expanded, plus the National Library of Medicine's PubMed service.
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