Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma☆

Kedda, Mary-Anne; Shi, Jing; Duffy, David L.; Phelps, Stephanie J.; Yang, Ian A.; O'Hara, Kirrily; Fong, Kwun M.; Thompson, Philip J.

doi:10.1016/j.jaci.2004.02.008

Cited by 60 publications

(51 citation statements)

References 28 publications

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“…LTC4S encodes for the main enzyme specific to CysLT synthesis and has been extensively studied, especially a Duroudier et al polymorphism located )444 upstream of the ATG translation start site ()444 A>C, rs730012). 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).…”

Section: Lta4h and Ltc4smentioning

confidence: 99%

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: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…2). In this example, the LTC4S -444 A>C promoter polymorphism has been associated to a reduced risk for asthma exacerbations when compared with individuals homozygous for reference allele (Sampson et al, 2000;Whelan et al, 2003;Husain et al, 2007); in other studies this observation was not consistent (Currie et al, 2003;Kedda et al, 2004) (Fig. 2).…”

Section: Asthmamentioning

confidence: 62%

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

Ceci¹,

Catapano²,

Manfredi³

et al. 2011

Drug Development - A Case Study Based Insight Into Modern Strategies

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“…In a study of a Japanese population, although the frequency of the variant C allele was significantly higher in AIA (q = 0.19) than in ATA patients (q = 0.11, p = 0.42), there was no significant relationship between the LTC4S -444A>C polymorphism and LTC4S activity (Kawagishi et al 2002). Recently, Kedda et al (2004) showed that the polymorphic LTC4S -444A>C was weakly associated with asthma per se in an Australian population, but found no association between the C -444 allele and chronic asthma severity or aspirin tolerance. Also, there were no significant differences detected in functional studies.…”

Section: Discussionmentioning

confidence: 96%

“…In contrast, no significant associations were detected in American (Van Sambeek et al 2000), Japanese (Kawagishi et al 2002), Australian (Kedda et al 2004), or Spanish (Isidoro-García et al 2005 populations. We also did not find an association between LTC4S -444A>C and AIA in a Korean population (Choi et al 2004).…”

mentioning

confidence: 96%

Lack of an Association between a Newly Identified Promoter Polymorphism (-1702G > A) of the Leukotriene C4 Synthase Gene and Aspirin-Intolerant Asthma in a Korean Population

Choi

Kim

Bae

et al. 2006

Tohoku J. Exp. Med.

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Aspirin-intolerant asthma (AIA) is a distinct clinical syndrome that refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). It is widely recognized that increased cysteinyl leukotriene (cysLT) biosynthesis is associated with the development and progression of AIA. Leukotriene C4 synthase (LTC4S) is the terminal enzyme in cysLT production and is a strong candidate gene in the pathogenesis of aspirin-intolerant asthma (AIA). In this paper, we report a new single nucleotide polymorphism (SNP) of the LTC4S promoter, -1702G>A, in AIA patients and evaluate its genetic role in the association with the LTC4S -444 A>C polymorphism. We enrolled 110 AIA patients, 125 aspirin-tolerant asthma (ATA) patients, and 125 normal controls. SNP genotyping of the LTC4S-1702G>A and -444A>C polymorphisms was performed using SNP-IT ™ assays. Haplotype analyses were performed using Haploview version 2.05, which is based on an estimation-maximization (EM) algorithm. There were no significant differences in the allele or genotype frequencies of the LTC4S -1702G>A and -444A>C polymorphisms among the three groups ( p > 0.05), with no significant differences in the observed haplotype frequencies ( p > 0.05). Moreover, no significant associations were found between the genotype of each SNP in AIA patients with the clinical characteristics, including a forced expiratory volume in one second (FEV 1 ) %, a provocation concentration of methacholine to induce more than 20% decrease of FEV 1 (PC 20 ) to methacholine, and serum total IgE levels ( p > 0.05). These results indicate that there is no association between these two promoter polymorphisms of LTC4S and the phenotype of AIA in a Korean population.aspirin-intolerant asthma; genetic polymorphism; leukotriene C4 synthase

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Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma☆

Cited by 60 publications

References 28 publications

Leukotriene pathway genetics and pharmacogenetics in allergy

Leukotriene pathway genetics and pharmacogenetics in allergy

Changes in Research and Development of Medicinal Products since the Paediatric Regulation

Lack of an Association between a Newly Identified Promoter Polymorphism (-1702G > A) of the Leukotriene C4 Synthase Gene and Aspirin-Intolerant Asthma in a Korean Population

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