Novel Polymorphism of the 5-Lipoxygenase Activating Protein (FLAP) Promoter Gene Associated with Asthma

Koshino, Takeshi; Takano, Shizuko; Kitani, Seiichi; Ohshima, Nobuharu; Sugiyama, Yasuyuki; Takaishi, Toshiaki; Hirai, Koichi; Yamamoto, Kazuhiko; Morita, Yutaka

doi:10.1006/mcbr.1999.0147

Cited by 27 publications

(30 citation statements)

References 32 publications

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“…No associations were observed with asthma in a Caucasian cohort of 341 asthma families or basal transcription levels in a promoter reporter analysis (107). However, association was observed with asthma in a Japanese study with a greater frequency of the 21A allele in asthmatics compared to controls, which was statistically significant (p = 0.035) (111). The significance of this finding is questionable for the small size of the study (71 subjects and 71 controls).…”

Section: Alox5 and Alox5apmentioning

confidence: 86%

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: Alox5 and Alox5apmentioning

confidence: 86%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…In patients with asthma, increased expression of ALOX5AP and ALOX5 mRNAs has been reported in peripheral blood leukocytes by the reverse transcriptionpolymerase chain reaction (RT-PCR) technique (Koshino et al 1998). Koshino et al (1999) have shown that the frequency of the monopolymer A repeats (21 A repeats, 95-73 bp upstream from the ATG transcription start site) in the polyadenyl region of the ALOX5AP promoter gene is significantly higher in asthmatics than in controls, but they have not identified the effects of these monopolymer A repeats of the ALOX5AP promoter gene on its promoter function. In this study, we have screened one known SNP of ALOX5AP+218A→G but have not found any association between ALOX5AP+218A→G and the AIA phenotype.…”

Section: Discussionmentioning

confidence: 99%

Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase

et al. 2004

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A recent study has demonstrated the possible involvement of a leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, whereas no significant association was noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls. The single-base extension method was used to genotype SNPs in 5-lipoxygenase (ALOX5, -1708G→A, 21C→T, 270G→A, 1728G→A), ALOX5-activating protein (ALOX5AP, 218A→G), prostaglandin-endoperoxide synthase 2 (PTGS2, COX2, -162C→G, 10T→G, R228H, V511A), LTC4S (-444A→C), and CYSLTR1 (927T→C). Haplotype analyses were undertaken for the SNPs in ALOX5. No significant differences in allele and genotype frequencies of single SNPs were observed between the patient groups (P>0.05). However, the frequency of the ALOX5-ht1 [G-C-G-A] haplotype in the AIA group was significantly higher than its frequency in the ATA group with a probability (P) of 0.01, odds ratio (OR) of 5.0, and 95% confidence interval (95%CI) of 1.54-17.9, and in the normal controls (P=0.03, OR=4.5, 95%CI=1.1-18.4), by using a dominant model. These results suggest a lack of association between the ALOX5AP, PTGS2, LTC4S, and CYSLTR1 gene polymorphisms and the AIA phenotype in the Korean population. However, the possible involvement of ALOX5-ht1 [G-C-G-A] in AIA development is suggested.

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“…The locations of the 48 SNPs in the National Center for Biotechnology Information human genome assembly build 34 are listed in Supplementary Table 3 online. In addition to the SNPs, we typed a polymorphism consisting of a monopolymer A repeat in the ALOX5AP promoter region 20 .…”

Section: Screening For Snps In Alox5ap and Ld Mappingmentioning

confidence: 99%

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

et al. 2004

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NATURE GENETICS VOLUME 36 | NUMBER 3 | MARCH 2004 233Cardiovascular diseases (CVD) are the leading causes of death and disability in the developed world 1 , with an increasing prevalence due to the aging of the population and the obesity epidemic. More than 1 million deaths in the US alone were caused by myocardial infarction and stroke in 2003 (ref. 2). Some of the processes underlying myocardial infarction are now understood: it is generally attributed to atherosclerosis with arterial wall inflammation that ultimately leads to plaque rupture, fissure or erosion 3,4 . This process is known to involve diapedesis of monocytes across the endothelial barrier; activation of neutrophils, macrophage cells and platelets; and release of a variety of cytokines and chemokines 5,6 , but the genetic basis of the process has not yet been deciphered. Two different approaches have been used to search for genes associated with myocardial infarction. SNPs in candidate genes have been tested for association and have, in general, not been replicated or confer only a modest risk of myocardial infarction. Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect 7-9 . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 . This is an interesting cause of myocardial infarction, but the prevalence of this or other mutations in MEF2A outside this family remains to be determined.Here we report a genome-wide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction. Through suggestive linkage to a locus on chromosome 13q12-13, we identified the gene (ALOX5AP) encoding FLAP and found that a four-SNP haplotype in the gene confers a nearly two times greater risk of myocardial infarction and stroke. FLAP is a regulator 15 of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model 16 and in human studies 17,18 . Males had the strongest association to the at-risk haplotype, and male carriers of the at-risk haplotype also had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction. We confirmed the association of ALOX5AP with myocardial infarction in an independent cohort of British individuals with another haplotype. These results indicate that ALOX5AP is the first specific gene isolated that confers substantial population-attributable risk (PAR) of the complex traits of both myocardial infarction and stroke. We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13....

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Novel Polymorphism of the 5-Lipoxygenase Activating Protein (FLAP) Promoter Gene Associated with Asthma

Cited by 27 publications

References 32 publications

Leukotriene pathway genetics and pharmacogenetics in allergy

Leukotriene pathway genetics and pharmacogenetics in allergy

Leukotriene-related gene polymorphisms in ASA-intolerant asthma: an association with a haplotype of 5-lipoxygenase

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

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