Association analysis of cysteinyl-leukotriene receptor 2 (CYSLTR2) polymorphisms with aspirin intolerance in asthmatics

Park, Jong Suk; Chang, Hun Soo; Park, Choon-Sik; Lee, June-Hyuk; Lee, Yong Mok; Choi, Jung Hee; Park, Hae‐Sim; Kim, Lyoung Hyo; Park, Byung Lae; Choi, Young-Hee; Shin, Hyoung Doo

doi:10.1097/01.fpc.0000166456.84905.a0

Cited by 95 publications

(68 citation statements)

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“…Three groups have investigated combinations of SNPs from several genes of the 5-LO pathway. Associations of the CYSLTR2 )819 G, 2078 T, 2534 G alleles with aspirin sensitivity were greater when combined with the LTC4S )444 C allele (135). Similarly, the combination of TA (927 CYSLTR1/)444 LTC4S) was significantly less common in male patients with asthma than in controls (OR = 0.37; p = 0.039) (123).…”

Section: Haplotype and Multi-snp Analysesmentioning

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: Haplotype and Multi-snp Analysesmentioning

confidence: 99%

“…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%

Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…This association of the CysLT 2 R M201V variant with airway disease has been independently replicated in a large outbred population (Pillai et al, 2004). Transmission disequilibrium testing in 137 Japanese asthmatic families revealed that the Ϫ1220AϾC polymorphism of the CYSLTR2 gene is associated with the development of asthma (Fukai et al, 2004), whereas four other sequence variants (either in the 5Ј-or 3Ј-flanking region or downstream of the gene) are associated with AIA (Park et al, 2005) and have been linked to altered CysLT 2 R expression (Shin et al, 2009). It is noteworthy that two other CYSLTR2 gene variants, in association with an ALOX5 polymorphism, have been shown to increase the response to montelukast (Klotsman et al, 2007).…”

mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

Bäck¹,

Dahlén²,

Drazen³

et al. 2011

Pharmacol Rev

130

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“…Besides parameters like efficiency and efficacy, drug metabolism has also been monitored. [1][2][3] Some of the genetic data generated during drug development can often be used for the identification of biomarkers, which provide a basis for diagnostic and prognostic tests. 4,5 Recently, microRNAs (miRNA) were found to be involved in disease development and progression.…”

mentioning

confidence: 99%