Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

In, Kwang Ho; Asano, Koichiro; Beier, David R.; Grobholz, J; Silverman, Edward; Silverman, Eric S.; Collins, Tucker; Fischer, Andreas; Keith, Tim P.; Serino, K; Kim, S W; Sanctis, George T. De; Yandava, Chandri; Pillari, Anthony; Rubin, Paul; Kemp, James P.; Israel, Elliot; Busse, William W.; Ledford, D; Murray, Ji; Segal, Anthony W.; Tinkleman, D; Drazen, Jeffrey M.

doi:10.1172/jci119241

Cited by 316 publications

(168 citation statements)

References 22 publications

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“…À1708G/A (no rs available designation) Modifying gene transcription with an increased protein expression (In et al, 1997) release of IL-10 observed in these high (+896A+) responder cell cultures (n = 10, r = À0.203, p = 0.023, data not shown). Thus, the possible reasons for this correlation might be the important contribution of biological effect of the SNP.…”

Section: -Lo (Nm-000698)mentioning

confidence: 99%

“…Changes in eicosanoid levels are also correlated with SNPs in the promoter region of PTGS2 and 5-Lo genes, respectively codifying the cyclooxygenase-(Cox)-2 and 5-lipoxygenase (5-Lo), enzymes involved in arachidonic acid metabolism. Two functional (À765G/C PTGS2 and À1708G/A 5-Lo) SNPs have recently been identified and associated with the major age-related diseases (Candore et al, 2007a,b;Caruso et al, 2009;Cipollone et al, 2004;In et al, 1997;Orbe et al, 2006). To clarify and confirm the possible pathophysiological effects of +896A/G TLR4 SNP (Balistreri et al, 2004(Balistreri et al, , 2010, we analysed the levels of IL-6, TNF-a, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of +896A/G TLR4 SNP.…”

Section: Introductionmentioning

confidence: 99%

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LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

Balistreri

Caruso

Listı́

et al. 2011

Mechanisms of Ageing and Development

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Section: -Lo (Nm-000698)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

Balistreri

Caruso

Listı́

et al. 2011

Mechanisms of Ageing and Development

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“…The ALOX5 5¢UTR has been well characterised and by resequencing asthma patient DNA samples mutations in the region 176-146 bp upstream of the ATG (in a GC-rich region) with deletion of one, or two or addition of one zinc finger (Sp1/Egr-1) binding sites have been identified which results in reduced Sp1/Egr-1 transcription factor binding and gene transcription (103,104). Mutations of the Sp1 repeat in the promoter are associated with airway hyperresponsiveness, but not asthma susceptibility (105,106).…”

Section: Alox5 and Alox5apmentioning

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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“…In et al (1997) first identified the promoter polymorphism of the ALOX5 gene consisting of a variable number of tandem repeats of GC-rich motifs associated with the binding of Sp1 transcription factors subjects with the wildtype genotype (five repeats) had a significantly higher capacity to produce Cys-LTs compared to those with a mutant genotype (3, 4, or 6 repeats). Furthermore, a significant association between the ALOX5 promoter polymorphism and the severity of airway hyperresponsiveness was detected in a Korean population (Kim et al 2005); When we screened ten SNPs for key enzymes involved in arachidonate metabolism, 5-lipoxygenase ( A L O X 5 , -1 7 0 8 G > A , 2 1 C > T, 2 7 0 G > A , 1 7 2 8 G > A ) , A L O X 5 -a c t i v a t i n g p r o t e i n (ALOX5AP, 218A>G), and cyclooxygenase 2 (COX-2, -162C>G, 10T>G, 228G>A), in a Korean population, the lack of an association was noted between the ALOX5AP, COX-2, and CYSLTR1 gene polymorphisms, and the AIA phenotype (Choi et al 2004).…”

Section: Discussionmentioning

confidence: 99%

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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Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

Cited by 316 publications

References 22 publications

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

Leukotriene pathway genetics and pharmacogenetics in allergy

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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