title: Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies.
abstract: Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of theALOX5gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in theLTC4Sgene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of theCYSLTR2gene, encoding the Met201ValCYSLTR2receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ∼2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%.In vitrowork showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca2+flux and inositol phosphate generation. In addition, theCYSLTR1gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.
authors.affiliation: Biochemical Genetics and Metabolomics Laboratory, Department of Pediatrics, University of California, San Diego, La JollaCA, USA; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ONCanada.
authors.forename: Miles D
authors.initials: MD
authors.lastname: Thompson
authors.affiliation: Department of Health Sciences, San Paolo Hospital, Università degli Studi di Milano Milano, Italy.
authors.forename: Valerie
authors.initials: V
authors.lastname: Capra
authors.affiliation: Department of Physiology/Neuroscience, School of Medicine, Saint George's University Saint George's, Grenada.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Clunes
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano Milano, Italy.
authors.forename: G E
authors.initials: GE
authors.lastname: Rovati
authors.affiliation: Division of Immunology and Allergy, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke QC, Canada.
authors.forename: Jana
authors.initials: J
authors.lastname: Stankova
authors.affiliation: Department of Biochemistry, School of Medicine, Saint George's University Saint George's, Grenada.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Maj
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston QLD, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Duffy
keywords: Tristan da Cunha; cysteinyl leukotriene 1 (CYSLTR1); cysteinyl leukotriene 2 (CYSLTR2); epigenetics; epistasis; montelukast; pharmacogenetics; pharmacogenomics