Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma.
OBJECTIVE
Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C4 synthase is a key enzyme in their biosynthesis. Our aim is to evaluate whether responsiveness to leukotriene receptor antagonists was determined by expression of the variant (C) or wild-type (A) polymorphism of this enzyme.


METHODS
We carried out a retrospective analysis of 8 randomised, placebo-controlled trials performed in our department in mild-to-moderate asthmatics. In all trials, effect of leukotriene receptor antagonist was compared to placebo, where the primary outcome was bronchial hyperresponsiveness to adenosine monophosphate or methacholine. Secondary outcomes were forced expiratory volume in 1 second, exhaled nitric oxide and peripheral blood eosinophils.


RESULTS
For the primary outcome of attenuation of bronchial hyperresponsiveness by leukotriene receptor antagonist vs placebo, there were significant effects within each genotype on adenosine monophosphate (AMP) (n = 78): 2.21 and 2.07-fold improvements for AA and AC/CC, respectively; while for methacholine (n = 81) there were 1.39 and 1.36-fold improvements, respectively. There were no significant differences between genotypes (i.e. AA vs AC/CC): geometric mean fold-differences of 1.07 (95%CI 0.63-1.81) and 1.02 (95%CI 0.70-1.50) for AMP and methacholine, respectively. There were also no differences between genotypes for all secondary outcomes.


CONCLUSIONS
Polymorphisms of leukotriene C4 synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists in mild-to-moderate asthmatics. Further prospective large pharmacogenetic studies are required in more severe patients, where there may be greater improvements in pharmacodynamic outcome measures such as bronchial hyperresponsiveness and exhaled nitric oxide.
Currie
Graeme P
GP
Asthma & Allergy Research Group, Ninewells Hospital & Medical School, University of Dundee, Dundee, UK.
Lima
John J
JJ
Sylvester
Jim E
JE
Lee
Daniel K C
DK
Cockburn
Wendy J R
WJ
Lipworth
Brian J
BJ
D000249:Adenosine Monophosphate; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D001980:Bronchi / Q000187:drug effects; D001985:Bronchial Provocation Tests; D001993:Bronchodilator Agents; D018592:Cross-Over Studies; D005541:Forced Expiratory Volume / Q000502:physiology; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D020024:Leukotriene Antagonists; D016210:Methacholine Chloride; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies
D001993:Bronchodilator Agents; D020024:Leukotriene Antagonists; D016210:Methacholine Chloride; D000249:Adenosine Monophosphate; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase