A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma

Pillai, Sreekumar; Cousens, Diane J.; Barnes, Ashley; Buckley, Peter T.; Chiano, Mathias; Hosking, Louise K.; Cameron, L.A.; Fling, Mary E.; Foley, James J.; Green, Andrew; Sarau, Henry M.; Schmidt, Dulcie B.; Sprankle, Catherine S.; Blumenthal, Malcolm N.; Vestbo, Jørgen; Kennedy-Wilson, Karen; Wixted, William E.; Wagner, Michael J.; Anderson, Wayne H.; Ignar, Diane M.

doi:10.1097/00008571-200409000-00007

Cited by 51 publications

(45 citation statements)

References 40 publications

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“…Multiple SNPs within CYSLTR2 have been found to be in association with atopic asthma or aspirin sensitivity within asthma subjects (134)(135)(136)(137). Interestingly, a coding region variant (601 A>G) results in a decreased potency for LTD 4 and was shown to be under transmitted to asthma subjects using 384 asthma families (136).…”

Section: Cyslt Receptorsmentioning

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: Cyslt Receptorsmentioning

confidence: 99%

“…Interestingly, a coding region variant (601 A>G) results in a decreased potency for LTD 4 and was shown to be under transmitted to asthma subjects using 384 asthma families (136). The Met201Val variant was also associated with atopy (137).…”

Section: Cyslt Receptorsmentioning

confidence: 99%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…The ascertainment procedure for the Danish collection is described elsewhere. 22 Replication population A total of 342 families ascertained from the United Kingdom as a part of the Genetics of Asthma International Network (GAIN) were selected as a replication population. Four sets of samples collected from the different centers: 94 families with 401 subjects from Aberdeen, UK; 73 families with 301 subjects from Leicester, UK; 93 families with 399 subjects from Sheffield, UK and 82 families with 345 subjects from Stoke-on-Trent, UK.…”

Section: Study Populations and Phenotypesmentioning

confidence: 99%

Interleukin 18 receptor 1 gene polymorphisms are associated with asthma

et al. 2008

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The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131rPr0.01377), five with atopic asthma (0.00066rPr0.00405) and two with BHR (0.01450rPr0.03203) in the Danish population; two SNPs were associated with atopic asthma (0.00397rPr0.01481) and four with BHR (0.00435rPr0.03544) in the UK population; four SNPs showed associations with asthma (0.00015rPr0.03062), two with atopic asthma (0.01269rPr0.04042) and three with BHR (0.00259rPr0.01401) in the Norwegian population; five SNPs showed associations with asthma (0.00005rPr0.03744), five with atopic asthma (0.00001rPr0.04491) and three with BHR (0.03568rPr0.04778) in the combined population. Three intronic SNPs (rs1420099, rs1362348 and rs1974675) showed replicated association for at least one asthma-related phenotype. These results demonstrate significant association between polymorphisms in IL18R1 and asthma.

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“…The primary study popula- 17,18 Appropriate institutional review boards approved the studies and appropriate informed consent was obtained from the human subjects. The clinical characteristics of the ascertained families are shown in Table 4.…”

Section: Study Populationsmentioning

confidence: 99%

Association of PTGDR gene polymorphisms with asthma in two Caucasian populations

et al. 2007

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The prostanoid DP receptor (PTGDR) is shown to be involved in the asthma patho-physiology and the results from the published genetic association studies are inconsistent. Four single nucleotide polymorphisms (SNPs) in PTGDR were genotyped in 342 and 294 families from UK and Denmark respectively. Asthma and asthma-related phenotypes were analyzed using family-based association analyses. In the UK families, a promoter polymorphism (À731A/G) showed significant associations with asthma (P ¼ 0.0022), atopic asthma (P ¼ 0.0044), bronchial hyperreactivity or BHR (P ¼ 0.00120) and strict asthma (P ¼ 0.0008). The P-values for asthma, BHR and strict asthma were significant even after the most stringent correction for the number of markers and the number of phenotypes analyzed (o0.0031). An intronic polymorphism ( þ 6651C/T) also showed significant associations with asthma (P ¼ 0.0302), atopic asthma (P ¼ 0.0131), BHR (P ¼ 0.0249) and strict asthma (P ¼ 0.0261). In the Danish families, an intronic polymorphism ( þ 6541C/T) showed significant associations with asthma (P ¼ 0.0071), atopic asthma (P ¼ 0.0348), BHR (P ¼ 0.0033) and strict asthma (P ¼ 0.0381). The results of haplotype analyses supported the ones of the single SNP analyses. Thus, we demonstrated significant evidence of association between polymorphisms in PTGDR with asthma phenotypes in the two Caucasian populations.

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A coding polymorphism in the CYSLT2 receptor with reduced affinity to LTD4 is associated with asthma

Abstract: Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy.

Cited by 51 publications

References 40 publications

Leukotriene pathway genetics and pharmacogenetics in allergy

Leukotriene pathway genetics and pharmacogenetics in allergy

Interleukin 18 receptor 1 gene polymorphisms are associated with asthma

Association of PTGDR gene polymorphisms with asthma in two Caucasian populations

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