Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma

Asano, Koichiro; Shiomi, Tetsuya; Hasegawa, Naoki; Nakamura, Hidetoshi; Kudo, Hiroko; Matsuzaki, Tatsu; Hakuno, Haruhiko; Fukunaga, Kouichi; Suzuki, Yusuke; Kanazawa, Minoru; Yamaguchi, Kazuhiro

doi:10.1097/00008571-200210000-00009

Cited by 133 publications

(92 citation statements)

References 13 publications

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“…Five of the nine published pharmacogenetic studies on the LTC4S )444 A>C polymorphism showed an improved response to LTRAs from patients carrying the C allele (116,119,122,142,146), although results were not always statistically significant (116,122,146) (perhaps partly due to the small number of individuals in the populations studied). The other four published studies could not reproduce these findings (144,145,147,148).…”

Section: Lt Pharmacogeneticsmentioning

confidence: 94%

“…Approximately half of the published genetic studies found the C allele associated with asthma, asthma severity or aspirin intolerance (105,(115)(116)(117)(118). The other studies, including two also investigating another promoter polymorphism ()1072 G>A) did not detect an association with those same phenotypes (109,(119)(120)(121)(122)(123)(124)(125)) (see Table 3). Interest- (113) 3¢UTR, 3¢ untranslated region; 5¢UTR, 5¢ untranslated region; A, asthma; AD, atopic dermatitis; AIA, aspirin intolerant asthma; AICU, aspirin intolerant chronic urticaria; AL, allergic; ALOX5, 5-lipoxygenase; ALOX5AP, 5-lipoxygenase activating protein; AR, allergic rhinitis; ATA, aspirin tolerant asthma; C, controls (population); C, coding region (location); I, intronic; LTA4H, leukotriene A4 hydrolase; LTC4S, leukotriene C4 synthase; NAL, nonallergic; P, promoter; SA, severe asthma; SNP, single nucleotide polymorphism.…”

Section: Lta4h and Ltc4smentioning

confidence: 99%

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Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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Leukotrienes (LT) are a family of potent eicosanoid lipid mediators with central importance in disease processes such as inflammation and proliferation most notably observed in allergic conditions like asthma (1). There are two general classes of LT according to the presence of a cysteine residue in their amino acid chain: the cysteinyl leukotrienes (CysLTs) including LTC 4 , LTD 4 and LTE 4 and the dihydroxyleukotriene LTB 4 (2). The 5-lipoxygenase pathwayLeukotrienes are produced in a multi-step enzyme pathway called the 5-lipoxygenase (5-LO) pathway, which is active in leucocytes such as neutrophils, eosinophils, mast cells and monocytes (Fig. 1). Arachidonic acid is the precursor for LT synthesis and is hydrolysed from the plasma membrane by cytosolic phospholipase A 2 (and other isoforms) (3, 4) in a calcium-dependent process (5). Upon activation, the rate-limiting enzyme 5-LO oxygenates first free arachidonic acid into the unstable intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE) which is then either hydrolysed to 5-hydroxyeicosatetraenoic acid (5-HETE) or transformed into the unstable epoxide leukotriene A 4 (LTA 4 ) by forming a conjugated triene system through dehydration (6). 5-LO translocates from either the nucleus (in macrophages) or cyotosol (in neutrophils) to the nuclear envelope in response to cell activation (7,8). This movement occurs as 5-LO is dependent on a 5-LO activating protein (FLAP) for its function. FLAP remains associated with the nuclear membrane (9) and acts as a Ôtransfer proteinÕ presenting arachidonic acid to 5-LO, a system which allows the favourable conversion of 5-HPETE to LTA 4 compared to 5-HETE (10). Both 5-LO and FLAP are expressed in cells of myeloid lineage (11) restricting the pathway to these cell types. LTA 4 can be further metabolised to the cysteinyl leukotrienes (CysLTs) or LTB 4 . The specific glutathione S-transferase leukotriene C 4 synthase (LTC 4 S) conjugates LTA 4 to form LTC 4 which can then be rapidly converted to LTD 4 by a gammaglutamyl transpeptidase and to LTE 4 by a dipeptidase once exported out the cell by membrane transport proteins such as multi-drug related protein 1 (MRP1) (12-15). A specific zinc metallohydrolase, LTA 4 hydrolase (LTA 4 H) is responsible for the conversion of LTA 4 to LTB 4 (16). CysLTs and LTB 4 act on different G-protein coupled receptors (GPCRs). Each bind to at least two different receptors: CysLTs to CYSLTR1 and CYSLTR2 and LTB 4 to LTB 4 R1 and LTB 4 R2 (or BLT1 and BLT2) (17).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. Leukotr...

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Section: Lt Pharmacogeneticsmentioning

confidence: 94%

Section: Lta4h and Ltc4smentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…A common polymorphism in the human LTC 4 S gene results from an A-C substitution 444 bases upstream of the translational start site. The presence of this polymorphism correlates with increased levels of LTC 4 generation by calcium ionophore-stimulated peripheral blood eosinophils (25), diminished lung function in asthmatic children (26), increased clinical responses to CysLT 1 receptor antagonists (25,27), and an increased incidence of aspirin sensitivity in some (28), but not all, human ethnic populations (29). Thus polymorphisms in cys-LT-generating enzymes may modify drug responses and certain phenotypic features in patients with asthma.…”

Section: Cys-lt Biosynthesismentioning

confidence: 99%

Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses

Kanaoka

Boyce

2004

The Journal of Immunology

298

266

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The cysteinyl leukotrienes (cys-LTs) are a family of potent bioactive lipids that act through two structurally divergent G protein-coupled receptors, termed the CysLT1 and CysLT2 receptors. The cloning and characterization of these two receptors has not only reconciled findings of previous pharmacologic profiling studies of contractile tissues, but also has uncovered their expression on a wide array of circulating and tissue-dwelling leukocytes. With the development of receptor-selective reagents, as well as mice lacking critical biosynthetic enzymes, transporter proteins, and the CysLT1 receptor, diverse functions of cys-LTs and their receptors in immune and inflammatory responses have been identified. We review cys-LT biosynthesis; the molecular biology and distribution of the CysLT1 and CysLT2 receptors; the functions of cys-LTs and their receptors in the recruitment and activation of effector leukocytes and induction of adaptive immunity; and the development of fibrosis and airway remodeling in animal models of lung injury and allergic inflammation.

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“…The mechanisms underlying interpatient variability in response are not clear but are believed to be due, in part, to genetic variability (8-11). Indeed, several studies have reported that promoter polymorphisms in the ALOX5 (12) and the LTC 4 synthase (LTC4S) genes contribute to variability in response to LT modifiers and LT selective antagonists (13)(14)(15)(16).CysLTs are potent mediators of asthma inflammation and are synthesized from arachidonic acid located in membrane-phospholipids by cytosolic phospholipase A 2 in response to stimulation (17,18). Arachidonic acid is converted to 5-hydroperoxyeicosatetraenoic acid and LTA 4 by membrane-bound 5-lipoxygenase (ALOX5) and 5-lipoxygenase activating protein (19).…”

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confidence: 99%

Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

Lima

Zhang

Grant

et al. 2006

Am J Respir Crit Care Med

213

226

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Rationale: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes. Objective: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial. Methods: Polymorphisms were typed using Sequenom matrixassisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism-expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, 2 and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test. Measurements: Outcomes were asthma exacerbation rate and changes in FEV 1 compared with baseline. Results: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV 1 (p Ͻ 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found. Conclusions: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response. Keywords: antiinflammatory; montelukast; pharmacodynamic; pharmacogeneticMontelukast is a selective cysteinyl leukotriene 1 (cysLT 1 ) receptor antagonist (1). Montelukast is recommended as an alternative to low-dose inhaled corticosteroids for patients with mild persis- tent asthma and recommended as alternative add-on (to inhaled corticosteroids) treatment in patients with moderate persistent (step 3) and severe persistent (step 4) asthma (2). Numerous clinical trials in adults and children with asthma have established the efficacy and safety of montelukast (3, 4). However, interpatient variability in response to montelukast in both children and adults with asthma is significant, with 35 to 78% of patients receiving montelukast being classified as nonresponders (5-7). The mechanisms underlying interpatient variability in response are not clear but are believed to be due, in part, to genetic variability (8-11). Indeed, several studies have reported that promoter polymorphisms in the ALOX5 (12) and the LTC 4 synthase (LTC4S) genes contribute to variability in response to LT modifiers and LT selective antagonists (13)(14)(15)(16).Cy...

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Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma

Cited by 133 publications

References 13 publications

Leukotriene pathway genetics and pharmacogenetics in allergy

Leukotriene pathway genetics and pharmacogenetics in allergy

Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses

Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma

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