Clinical and genetic features underlying the response of patients with bronchial asthma to treatment with a leukotriene receptor antagonist

Mastalerz, Lucyna; Nizankowska, E; Sanak, Marek; Mejza, Filip; Pierzchalska, Małgorzata; Bazan-Socha, Stanisława; Bestynska-Krypel, A.; Ćmiel, Adam; Szczeklik, Andrzej

doi:10.1046/j.1365-2362.2002.01088.x

Cited by 58 publications

(41 citation statements)

References 26 publications

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“…CYSLTR1 promoter SNPs are located from the exon 4 3¢end as described by Duroudier et al (133). (122,125). In Asian populations, aspirin sensitive asthma patients showed a higher frequency of the C allele in one study (270 individuals, p = 0.042), but this could not be reproduced elsewhere (109,120).…”

Section: Lta4h and Ltc4smentioning

confidence: 91%

“…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: 93%

“…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: Lta4h and Ltc4smentioning

confidence: 91%

Section: Lt Pharmacogeneticsmentioning

confidence: 93%

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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“…zileuton (unavailable in the United Kingdom). There is a spectrum of individual responsiveness to LTRAs that is currently not predictable [100][101][102]. Therapeutic profile similar to antihistamines, with efficacy comparable to loratadine in SAR [103].…”

Section: Anti-leukotrienesmentioning

confidence: 99%

BSACI guidelines for the management of allergic and non‐allergic rhinitis

Scadding

Durham

Mirakian

et al. 2007

Clin Experimental Allergy

348

292

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SummaryThis guidance for the management of patients with allergic and non-allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web-based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co-morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research.

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“…A gene promoter polymorphism (A-444C, rs730012) has been previously associated with increased production and expression of LTC 4 by blood eosinophils (C allele) [44]. 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].…”

Section: Leukotriene C 4 Synthase (Ltc4s)mentioning

confidence: 98%