Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast

Klotsman, Michael; York, Timothy P.; Pillai, Sreekumar; Vargas-Irwin, Cristina; Sharma, Sanjay; Oord, Edwin J. C. G. van den; Anderson, Wayne H.

doi:10.1097/fpc.0b013e3280120043

Cited by 104 publications

(89 citation statements)

References 51 publications

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“…The other four published studies could not reproduce these findings (144,145,147,148). As these results were obtained in different populations and using different end points, this suggests that, although not sufficient to explain the variation in patient response to LTRAs, this polymorphism is a strong candidate and is potentially exerting its influence with other gene polymorphisms.…”

Section: Lt Pharmacogeneticscontrasting

confidence: 42%

“…Another study found no polymorphism specific bronchodilator responses between homozygous wildtypes and heterozygotes for the ALOX5 Sp1 polymorphism in 52 asthma subjects (143). Kim et al found no significant association between LTRA requirement and polymorphisms in the ALOX5 gene and Klotsman et al identified an 18-25% improvement in peak expiratory flow for mutant alleles of ALOX5 SNP rs4987105 and rs4986832 (p = 0.01 for both), whereas wild-type patients only showed a 10% improvement (144,145). These data illustrated that genes regulating the expression of LTs could influence the efficacy of therapeutics that target their synthesis and/or activity and further studies are required to determine the role of ALOX5 polymorphisms on these responses.…”

Section: Lt Pharmacogeneticsmentioning

confidence: 99%

“…In a Korean population of 100 children with exercise-induced asthma, the synonymous coding CYSLTR1 polymorphism T>C (rs320995) did not affect the efficacy of montelukast to improve FEV 1 (148), but the minor alleles of both the promoter and coding SNPs [C>T (rs321029) and T>C (rs320995)] were associated with requirement for montelukast in another Korean population of 89 aspirin intolerant asthmatics (p < 0.02) (144). Carriers of the variants of two polymorphisms in the CYSLTR1 gene (rs91227 and rs912278) responded better to montelukast (145).…”

Section: Lt Pharmacogeneticsmentioning

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: Lt Pharmacogeneticscontrasting

confidence: 42%

Section: Lt Pharmacogeneticsmentioning

confidence: 99%

Section: Lt Pharmacogeneticsmentioning

confidence: 99%

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Leukotriene pathway genetics and pharmacogenetics in allergy

Duroudier

Tulah

Sayers

2009

Allergy

102

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“…In contrast, a study by Lima et al found that patients carrying 5 tandem repeats had an increased risk of exacerbations compared to patients carrying variant alleles [57]. Studies by Fowler et al and Klotsman et al reported no increased risk of poor montelukast response in patients carrying this genetic variant [54,58]. The effect of the ALOX5 promotor SP1 tandem repeat variant on treatment response seems to be context specific and may depend on the specific (non-5 tandem repeat) variant [59].…”

Section: Leukotriene Modifiers Responsementioning

confidence: 57%

“…Initially, candidate-gene studies on LTRA response focused on genes within pharmacological leukotriene pathway, such as leukotriene A4 hydrolase (LTC4s), 5-lipoxygenase (ALOX5), leukotriene A4 hydrolase (LTA4H), and cysteinyl leukotriene receptor 1 (CysLTR1) [41]. In addition, genes influencing LTM pharmacokinetics such as CYP enzymes (CYP3A4, CYP2C9) and transporter genes (SLCO2B1, MRP1/ ABCC1) have also been investigated [53,54]. A recent systematic review showed that despite a large amount of pharmacogenetics LTRA studies; only variants in two genes, ALOX5 and MRP1, have been replicated to show similar outcomes of LTRA response at least once [41].…”

Section: Leukotriene Modifiers Responsementioning

confidence: 99%

Treatment response heterogeneity in asthma: the role of genetic variation

Vijverberg

Farzan

Slob

et al. 2017

Expert Review of Respiratory Medicine

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Introduction: Asthmatic patients show a large heterogeneity in response to asthma medication. Rapidly evolving genotyping technologies have led to the identification of various genetic variants associated with treatment outcomes. Areas covered: This review focuses on the current knowledge of genetic variants influencing treatment response to the most commonly used asthma medicines: short-and long-acting beta-2 agonists (SABA/ LABA), inhaled corticosteroids (ICS) and leukotriene modifiers. This review shows that various genetic variants have been identified, but none are currently used to guide asthma treatment. One of the most promising genetic variants is the Arg16 variant in the ADRB2 gene to guide LABA treatment in asthmatic children. Expert commentary: Poor replication of initially promising results and the low fraction of variability accounted for by single genetic variants inhibit pharmacogenetic findings to reach the asthma clinic. Nevertheless, the identification of genetic variation influencing treatment response does provide more insights in the complex processes underlying response and might identify novel targets for treatment. There is a need to report measures of clinical validity, to perform precision-medicine guided trials, as well as to understand how genetic variation interacts with environmental factors. In addition, systems biology approaches might be able to show a more complete picture of these complex interactions.ARTICLE HISTORY

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