Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma

Kang, Mi‐Jin; Kwon, Ji‐Won; Kim, Byoung-Ju; Yu, Jinho; Choi, Wonjun; Shin, Young-jeon; Hong, Soo‐Jong

doi:10.1038/jhg.2011.3

Cited by 22 publications

(23 citation statements)

References 33 publications

(54 reference statements)

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“…The LTMs used to treat asthma, such as montelukast, a drug which targets cysteinyl leukotriene 1 (CYSLTR1) receptor protein, have a greater than 20% non-response rate (Noonan et al, 1998). While some of the pharmacogenetic determinants of LTM response are attributable to variability in genes that are integral (Kang et al, 2011; Mougey et al, 2013) to the signaling of cysteinyl leukotrienes ( Figure 1 ), many true pharmacogenetic variants are located in genes that lie directly outside the pathway (Dahlin et al, 2015, 2016). …”

Section: Introductionmentioning

confidence: 99%

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies

et al. 2016

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Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the ALOX5 gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the LTC4S gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the CYSLTR2 gene, encoding the Met201Val CYSLTR2 receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ∼2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. In vitro work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca2+ flux and inositol phosphate generation. In addition, the CYSLTR1 gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.

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Section: Introductionmentioning

confidence: 99%

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies

et al. 2016

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“…Five of the ten published pharmacogenetic studies on the LTC4S -444 A>C polymorphism showed an improved response to LTRAs (FEV 1 ) from patients carrying the C allele [42,[44][45][46][47], although results were not always statistically significant [44,46,47]. The other five published studies could not reproduce these findings [43,[48][49][50][51]. More recently, a study of zileuton responses (FEV 1 change over time) in 577 asthma subjects failed to identify a pharmacogenetic effect of the LTC4S-444 polymorphism.…”

Section: Leukotriene C 4 Synthase (Ltc4s)mentioning

confidence: 53%

Genetic basis for personalized medicine in asthma

Portelli

Sayers²

2012

Expert Review of Respiratory Medicine

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“…Pharmacogenomic studies on response to LTRA have found most association with ALOX5 ,93,94 a 5-lipoxygenase, and LTC4S , a glutathione S-transferase 95,96. However, a step closer to clinical implementation is the assessment of the beta-adrenergic receptor gene ( ADRB2 ) in order to determine response to β2-agonists, for which randomized clinical trial (RCT) data are available 97–99.…”

Section: Biomarkers Under Developmentmentioning

confidence: 99%

Clinical utility of asthma biomarkers: from bench to bedside

Vijverberg¹,

Hilvering²,

Raaijmakers³

et al. 2013

BTT

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Asthma is a chronic disease characterized by airway inflammation, bronchial hyperresponsiveness, and recurrent episodes of reversible airway obstruction. The disease is very heterogeneous in onset, course, and response to treatment, and seems to encompass a broad collection of heterogeneous disease subtypes with different underlying pathophysiological mechanisms. There is a strong need for easily interpreted clinical biomarkers to assess the nature and severity of the disease. Currently available biomarkers for clinical practice – for example markers in bronchial lavage, bronchial biopsies, sputum, or fraction of exhaled nitric oxide (FeNO) – are limited due to invasiveness or lack of specificity. The assessment of markers in peripheral blood might be a good alternative to study airway inflammation more specifically, compared to FeNO, and in a less invasive manner, compared to bronchoalveolar lavage, biopsies, or sputum induction. In addition, promising novel biomarkers are discovered in the field of breath metabolomics (eg, volatile organic compounds) and (pharmaco)genomics. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches in which the clinical value of a combination of various markers is studied. This could eventually lead to the development of a clinically applicable algorithm composed of various markers and clinical features to phenotype asthma and improve diagnosis and asthma management.

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Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma

Cited by 22 publications

References 33 publications

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies

Cysteinyl Leukotrienes Pathway Genes, Atopic Asthma and Drug Response: From Population Isolates to Large Genome-Wide Association Studies

Genetic basis for personalized medicine in asthma

Clinical utility of asthma biomarkers: from bench to bedside

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