Leukotriene pathway genetics and pharmacogenetics in allergy.
Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC(4), LTD(4) and, LTE(4)) and the dihydroxy leukotriene LTB(4) are generated by a series of enzymes/proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotriene receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have shown clinical efficacy in asthma and more recently in allergic rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory mediators remains to be fully understood. Genes encoding enzymes of the 5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for disease susceptibility and severity; however, their role remains unclear. Preliminary data also suggest that 5-LO pathway/receptor gene polymorphism can predict patient responses to LTSI and LTRA; however, the exact mechanisms require elucidation. The aim of this review was to summarize the recent advances in the knowledge of these important mediators, focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes.
Division of Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, UK.
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NP
Duroudier
A S
AS
Tulah
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Sayers
D058927:5-Lipoxygenase-Activating Proteins; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D001249:Asthma / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D004851:Epoxide Hydrolases / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D020024:Leukotriene Antagonists / Q000627:therapeutic use; D015289:Leukotrienes / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D018077:Receptors, Leukotriene / Q000235:genetics / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D018102:Receptors, Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; C041116:leukotriene-C4 synthase; C083169:leukotriene D4 receptor; C043134:leukotriene A4 hydrolase