Uncertain biologic relevance of polymorphisms of leukotriene C4 synthase in asthma
Authors: Graeme P. Currie, Daniel K.C. Lee
Journal: Journal of Allergy and Clinical Immunology (2005)

To the Editor:The study by Kedda et al1Kedda M.A. Shi J. Duffy D. Phelps S. Yang I. O'Hara K. et al.Characterization of two polymorphisms in the leukotriene C4 synthase gene an Australian population of subjects with mild, moderate and severe asthma.J Allergy Clin Immunol. 2004; 113: 889-895Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar provides some evidence that polymorphisms of leukotriene C4 synthase, a key enzyme in the biosynthesis of cysteinyl leukotrienes, have little relationship to markers of asthma severity.In this study the authors define asthma severity according to clinical parameters, such as FEV1, inhaled corticosteroid dose, and symptoms. However, it is important to be aware that symptoms and lung function tend to be downstream consequences of the asthmatic inflammatory process. Moreover, many patients with persistent asthma have normal lung function, despite demonstrating marked airway hyperresponsiveness (AHR),2Vignola A.M. Chanez P. Campbell A.M. Souques F. Lebel B. Enander I. et al.Airway inflammation in mild intermittent and in persistent asthma.Am J Respir Crit Care Med. 1998; 157: 403-409Crossref PubMed Scopus (283) Google Scholar, 3Boulet L.P. Turcotte H. Brochu A. Persistence of airway obstruction and hyperresponsiveness in subjects with asthma remission.Chest. 1994; 105: 1024-1031Crossref PubMed Scopus (108) Google Scholar which in turn is often the driving force behind episodic airflow obstruction with subsequent perception of symptoms. In view of this, it would have been of interest if the relationship between polymorphisms of leukotriene C4 synthase and surrogate biomarkers of inflammation, such as AHR to adenosine monophosphate and airway eosinophils, had also been evaluated.A retrospective analysis evaluated whether polymorphisms of leukotriene C4 synthase were related to response to leukotriene receptor antagonists (LTRAs) in asthmatic patients.4Currie G.P. Lima J.J. Sylvester J.E. Lee D.K.C. Cockburn W.J.R. Lipworth B.J. Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma.Br J Clin Pharmacol. 2003; 56: 422-426Crossref PubMed Scopus (42) Google Scholar This study demonstrated that LTRAs did not preferentially attenuate the primary outcome of AHR to either direct or indirect stimuli between patients with the variant (C) and wild-type (A) alleles. There were also no treatment differences between genotypes (A/A vs A/C or CC) in terms of effects on other surrogate biomarkers of inflammation or lung function. In turn, it would have been of interest if Kedda et al1Kedda M.A. Shi J. Duffy D. Phelps S. Yang I. O'Hara K. et al.Characterization of two polymorphisms in the leukotriene C4 synthase gene an Australian population of subjects with mild, moderate and severe asthma.J Allergy Clin Immunol. 2004; 113: 889-895Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar had prospectively examined whether a response to leukotriene antagonism, in terms of both surrogate biomarkers of inflammation and clinical parameters, was related to genotypes containing the variant allele.Thus whether polymorphisms of leukotriene C4 synthase are truly related to fundamental components driving the asthma inflammatory process remains uncertain. Further prospective data are also required to definitely determine whether clinical response to LTRAs are determined by polymorphisms (or combinations of polymorphisms) of leukotriene C4 synthase in asthmatic patients. To the Editor: The study by Kedda et al1Kedda M.A. Shi J. Duffy D. Phelps S. Yang I. O'Hara K. et al.Characterization of two polymorphisms in the leukotriene C4 synthase gene an Australian population of subjects with mild, moderate and severe asthma.J Allergy Clin Immunol. 2004; 113: 889-895Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar provides some evidence that polymorphisms of leukotriene C4 synthase, a key enzyme in the biosynthesis of cysteinyl leukotrienes, have little relationship to markers of asthma severity. In this study the authors define asthma severity according to clinical parameters, such as FEV1, inhaled corticosteroid dose, and symptoms. However, it is important to be aware that symptoms and lung function tend to be downstream consequences of the asthmatic inflammatory process. Moreover, many patients with persistent asthma have normal lung function, despite demonstrating marked airway hyperresponsiveness (AHR),2Vignola A.M. Chanez P. Campbell A.M. Souques F. Lebel B. Enander I. et al.Airway inflammation in mild intermittent and in persistent asthma.Am J Respir Crit Care Med. 1998; 157: 403-409Crossref PubMed Scopus (283) Google Scholar, 3Boulet L.P. Turcotte H. Brochu A. Persistence of airway obstruction and hyperresponsiveness in subjects with asthma remission.Chest. 1994; 105: 1024-1031Crossref PubMed Scopus (108) Google Scholar which in turn is often the driving force behind episodic airflow obstruction with subsequent perception of symptoms. In view of this, it would have been of interest if the relationship between polymorphisms of leukotriene C4 synthase and surrogate biomarkers of inflammation, such as AHR to adenosine monophosphate and airway eosinophils, had also been evaluated. A retrospective analysis evaluated whether polymorphisms of leukotriene C4 synthase were related to response to leukotriene receptor antagonists (LTRAs) in asthmatic patients.4Currie G.P. Lima J.J. Sylvester J.E. Lee D.K.C. Cockburn W.J.R. Lipworth B.J. Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma.Br J Clin Pharmacol. 2003; 56: 422-426Crossref PubMed Scopus (42) Google Scholar This study demonstrated that LTRAs did not preferentially attenuate the primary outcome of AHR to either direct or indirect stimuli between patients with the variant (C) and wild-type (A) alleles. There were also no treatment differences between genotypes (A/A vs A/C or CC) in terms of effects on other surrogate biomarkers of inflammation or lung function. In turn, it would have been of interest if Kedda et al1Kedda M.A. Shi J. Duffy D. Phelps S. Yang I. O'Hara K. et al.Characterization of two polymorphisms in the leukotriene C4 synthase gene an Australian population of subjects with mild, moderate and severe asthma.J Allergy Clin Immunol. 2004; 113: 889-895Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar had prospectively examined whether a response to leukotriene antagonism, in terms of both surrogate biomarkers of inflammation and clinical parameters, was related to genotypes containing the variant allele. Thus whether polymorphisms of leukotriene C4 synthase are truly related to fundamental components driving the asthma inflammatory process remains uncertain. Further prospective data are also required to definitely determine whether clinical response to LTRAs are determined by polymorphisms (or combinations of polymorphisms) of leukotriene C4 synthase in asthmatic patients.