Responsiveness to montelukast is associated with bronchial hyperresponsiveness and total immunoglobulin E but not polymorphisms in the leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes in Korean children with exercise‐induced asthma (EIA)

Lee, S.-Y.; Kim, H.-B.; Kim, J.-H.; Kim, B.-S.; Kang, Mi‐Jin; Jang, Seong Soo; Seo, Hyeonji; Hong, Soo‐Jong

doi:10.1111/j.1365-2222.2007.02795.x

Cited by 29 publications

(27 citation statements)

References 44 publications

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“…The other four published studies could not reproduce these findings (144,145,147,148). As these results were obtained in different populations and using different end points, this suggests that, although not sufficient to explain the variation in patient response to LTRAs, this polymorphism is a strong candidate and is potentially exerting its influence with other gene polymorphisms.…”

Section: Lt Pharmacogeneticscontrasting

confidence: 43%

“…In a Korean population of 100 children with exercise-induced asthma, the synonymous coding CYSLTR1 polymorphism T>C (rs320995) did not affect the efficacy of montelukast to improve FEV 1 (148), but the minor alleles of both the promoter and coding SNPs [C>T (rs321029) and T>C (rs320995)] were associated with requirement for montelukast in another Korean population of 89 aspirin intolerant asthmatics (p < 0.02) (144). Carriers of the variants of two polymorphisms in the CYSLTR1 gene (rs91227 and rs912278) responded better to montelukast (145).…”

Section: Lt Pharmacogeneticsmentioning

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 Pharmacogeneticscontrasting

confidence: 43%

Section: Lt Pharmacogeneticsmentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…Second, subjects were classified into PC 20 6 16 and PC 20 > 16 groups according to whether the value of the methacholine provocation test (PC 20 ) was above or below 16. Asthma was defined as PC 20 6 16 because PC 20 values below 16 represent BHR [12,13]. Peripheral blood was taken from all subjects for DNA isolation.…”

Section: Subjectsmentioning

confidence: 99%

GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophil-mediated bronchial hyperresponsiveness

Kang¹,

Yu²,

Seo³

et al. 2012

Human Immunology

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“…Five of the ten published pharmacogenetic studies on the LTC4S -444 A>C polymorphism showed an improved response to LTRAs (FEV 1 ) from patients carrying the C allele [42,[44][45][46][47], although results were not always statistically significant [44,46,47]. The other five published studies could not reproduce these findings [43,[48][49][50][51]. More recently, a study of zileuton responses (FEV 1 change over time) in 577 asthma subjects failed to identify a pharmacogenetic effect of the LTC4S-444 polymorphism.…”

Section: Leukotriene C 4 Synthase (Ltc4s)mentioning

confidence: 99%