***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: CysLT(1 ) antagonists are effective for a subset of patients with asthma ; however , there has been no good way to predict a given patient 's response . We examined the interaction between the clinical response to a cysLT(1 ) antagonist , pranlukast , and DNA sequence variant A(-444)C in leukotriene C(4 ) synthase ( LTC(4 ) S ) gene in Japanese patients with moderate asthma . The frequency of LTC(4 ) S C(-444 ) allele was 21.6 % in the Japanese general population ( n = 171 ) and 19.4 % in the asthmatic subjects ( n= 349 ) . A 4-week prospect i ve , open trial of pranlukast ( 225 mg twice daily ) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid ( beclomethasone 400 - 800 microg/day or fluticasone 200 - 400 microg/day ) . The C(-444 ) allele carriers ( n = 16 ) responded better to pranlukast compared to the A(-444 ) allele homozygotes ( n= 31 ) [ 14.3 5.3 % vs. 3.1 2.4 % improvement of forced expiratory volume in one second ( FEV(1 ) ) , 0.01 ] , while LTC(4 ) S genotype-stratified response to inhaled beta-agonist salbutamol ( 200 microg ) was not observed ( 17.5 2.1 % vs. 18.7 2.2 % improvement of FEV(1 ) ) . Univariate analysis demonstrated that the better response to pranlukast ( more than 10 % improvement of FEV(1 ) ) was correlated with LTC(4 ) S genotype ( P < 0.01 ) and pretreatment airway reversibility to salbutamol ( P < 0.01 ) , but not with sex , age , atopic status , urinary leukotriene E(4 ) excretion rate , or daily dose of inhaled corticosteroid . Furthermore , multivariate regression analysis suggested that LTC(4 ) S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast ( P < 0.05 ) . We conclude that LTC(4 ) S genotype is predictive of the clinical response to a cysLT(1 ) antagonist , pranlukast , in Japanese patients with moderate asthma The interpatient variability in response to asthma controllers is significant and associates with pharmacogenomic variability . The goal of the present study was to identify novel variants that associate with response to common asthma controllers : fluticasone , combination of fluticasone + salmeterol and montelukast with single nucleotide polymorphisms ( SNPs ) in β2-adrenergic receptor , corticosteroid and leukotriene pathway c and i date genes . Participants in a large clinical trial of step-down strategies volunteered for this pharmacogenetic study . A total of 169 SNPs in 26 c and i date genes were genotyped in 189 Caucasian participants with asthma who took either fluticasone ( 100 μg bid ) , fluticasone propionate ( 100 μg ) + salmeterol ( 50 μg ) ( FP/Salm ) or montelukast ( 5 or 10 mg ) each night for 16 weeks . Primary outcomes were the slopes of plots of Asthma Control Question naire ( ACQ ) scores versus time following r and omization ; and the percent change in percent predicted FEV1 ( ΔFEV1%pred ) from enrollment to the end of the study . Associations between SNPs and outcomes were analyzed using general linear models . False discovery rate and Bonferroni corrections were used to correct for multiple comparisons . In all , 16 SNPs in seven genes were significantly associated with outcomes . For FP/Salm , three SNPs in CHRM2 associated with ACQ slope ( P=2.8 × 10−5 ) , and rs1461496 in HSPA8 associated with ΔFEV1%pred . For fluticasone , five SNPs in CRHR1 ( P=1.9 × 10−4 ) , and three SNPs in COL2A1 associated with ACQ slope and ΔFEV1%pred , respectively . For montelukast , four SNPs in CHRM2 associated with ΔFEV1%pred and predicted an opposite effect compared with fluticasone ( P=9 × 10−3 ) . The present study indentified several novel SNPs that associate with response to common asthma controllers , and support further pharmacogenomic study and the use of genetic variants to personalize asthma treatment Objective Interindividual clinical response to leukotriene modifiers is highly variable , and less efficacious than inhaled corticosteroids in treating asthma . Genetic variability in 5-lipoxygenase biosynthetic and receptor pathway gene loci may influence cysteinyl-leukotriene production and subsequent response to leukotriene modifiers . Methods Using data from two clinical trials of 12-week duration , post-hoc analyses were performed in 174 patients r and omized to montelukast .  Associations between polymorphisms in 10 c and i date genes ( ALOX5 , ALOX5AP , LTC4S , CYSLTR1 , CYSLTR2 , PLA2G4A , CYP2C9 , CYP3A4 , ADRB2 , and NR3C1 ) and response to montelukast were modeled using change in morning peak expiratory flow and forced expiratory volume in 1 s ( FEV1 ) to define the response phenotype . Results In our sample , eight out of 25 markers in 10 c and i date genes were statistically associated with response to montelukast , with an estimated proportion of false discoveries of 16 % . The strongest statistical evidence of clinical ly relevant pharmacogenetic effects peak expiratory flow were identified in CYSLTR2 ( rs91227 and rs912278 ; P=0.02 and P=0.02 , respectively ) and ALOX5 ( rs4987105 and rs4986832 ; P=0.01 and P=0.01 , respectively ) . Patients with these variant genotypes , found in roughly 10–13 % of patients , had an 18–25 % improvement in peak expiratory flow . In contrast , the majority of patients with the wild-type alleles had only a marginal ( 8–10 % ) improvement . Conclusions The overall mean response to montelukast may be skewed towards a response phenotype by a small subset ( < 15 % ) of asthma patients . CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations , yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy . These findings require replication to establish validity and clinical utility For patients with persistent asthma , the National Asthma Education and Prevention Program recommends the regular use of controller medications to provide long-term control , together with as-needed use of rescue medications ( 1 ) . Inhaled corticosteroids are currently the most commonly used controller medications ( 1 ) . Although inhalation into the airway has advantages in terms of both safety and efficacy , problems with compliance with inhaled agents may limit their real-world effectiveness , especially in elderly and pediatric patients ( 2 , 3 ) . Cysteinyl leukotrienes are important pro-inflammatory mediators of asthma ( 4 ) . Recent clinical studies of leukotriene receptor antagonists ( 5 - 7 ) and a 5-lipoxygenase inhibitor ( 8) have shown these agents to have clinical benefit in patients with chronic asthma , and treatment guidelines now consider these agents alternative , first-line controller medications ( 1 ) . Recent studies showed that montelukast , a potent and specific leukotriene receptor antagonist ( 9 ) , had efficacy in adult ( over a 12-week period ) and pediatric ( over an 8-week period ) patient with chronic asthma and had a tolerability profile similar to that of placebo ( 10 - 12 ) . To date , no comparisons of leukotriene receptor antagonists and inhaled corticosteroids have been published . Our placebo-controlled , parallel-group study , which was primarily design ed to compare the effect of montelukast with that of placebo in a phase III clinical development trial , also compared montelukast and inhaled beclomethasone in patients with chronic asthma who require the daily use of a controller medication . Methods Patients Healthy , nonsmoking , male and female patients 15 years of age and older were eligible to participate if they had had asthma for at least 1 year before the initial study evaluation . Each patient also had to have 1 ) an FEV1 between 50 % and 85 % of predicted value , 2 ) an increase of at least 15 % in absolute FEV1 after the use of inhaled -agonist on at least two of three visits during period 1 [ see below ] , 3 ) a daytime asthma symptom score of at least 64 [ of a possible 336 ] , and 4 ) average daily use of at least one puff of as-needed , short-acting , inhaled -agonist ( salbutamol )  . Patients were excluded from the study if they had used inhaled and oral corticosteroids , cromolyn , or nedocromil within 4 weeks before the initial evaluation ; had used long-acting -agonists , antimuscarinics , and newly instituted theophylline within 2 weeks before the initial evaluation ; or had used long-acting antihistamines ( for example , they could not have used astemizole within 3 months of the initial evaluation , and they could not have used terfenadine or loratadine within 2 weeks of the initial evaluation ) . Intermittent use of short-acting antihistamines was allowed , and immunotherapy was permitted if it had been started at least 6 months before the initial study evaluation and if the monthly dose remained constant . Protocol Our r and omized , double-dummy , placebo-controlled , parallel-group trial had a 2-week , single-blind placebo run-in period ( period 1 ) ; a 12-week , double-blind treatment period ( period 2 ) ; and a 3-week , double-blind placebo washout period [ period 3 ] . Eligible patients were r and omly assigned to one of three treatment regimens : 1 ) montelukast , 10 mg once daily in the evening ; 2 ) inhaled beclomethasone , 200 g twice daily ; or 3 ) placebo . The ratio of montelukast recipients to beclomethasone recipients to placebo recipients was 3:2:2 , with a blocking factor of 7 , according to a single , computer-generated allocation schedule . Patients , investigators , and coordinating center staff were blinded to the treatment schedule until all corrections to the data base were completed . During period 3 , a subset of patients originally assigned to receive active treatment ( approximately 40 , as determined by the allocation schedule ) was switched to placebo in a blinded manner . The other patients originally assigned to receive active treatment continued to receive that treatment . This allowed us to assess withdrawal from therapy . The study was done at 36 clinical centers in 19 countries in Europe , Africa , Australia , Central America , and South America . The study protocol and informed consent were approved by local ethics review committees . All participants gave written informed consent before participation ; consent of parents or guardians was obtained for patients younger than 18 years of age . Patients were recruited from the patient pool of each clinical study center and through local newspaper advertisements . Medication The study medication consisted of 10-mg montelukast film-coated tablets , placebo tablets that were identical in appearance to the montelukast tablets , beclomethasone ( 100 g/puff ) in inhalers ( Allen & Hanburys , Stockley Park , United Kingdom ) , and placebo in inhalers identical to those used for beclomethasone . Patients were instructed to take one tablet at bedtime and to take two puffs from the inhaler ( using the AeroChamber spacer device [ Clement Clark , Columbus , Ohio ] ) at bedtime and in the morning . Short-acting , inhaled -agonist ( salbutamol , 100 g/puff ) ( Allen & Hanburys ) was to be used as needed . Patients with worsening episodes of asthma that required additional therapy were treated with oral corticosteroids according to a st and ard protocol . Patients who had more than two worsening episodes of asthma requiring corticosteroid therapy were dropped from the study . Measurements Central ized spirometry training was done according to st and ard American Thoracic Society criteria before the start of the study .  Spirometry  was done at each visit after inhaled -agonist therapy had been withheld for at least 6 hours , theophylline therapy had been withheld for at least 24 hours , and antihistamine therapy had been withheld for at least 48 hours . At least three spirometry maneuvers were done , and the largest FEV1 was reported . Spirometry data were transmitted electronically to a central data base and monitored continuously for quality , and feedback was given to the study centers ( 13 ) . If quality was not maintained , sites were visited by coordinating center personnel . Answers to four questions on daytime asthma symptoms and one question on nocturnal awakenings were collected on a daily diary card , as were morning and evening peak expiratory flow rate and daily use of as-needed salbutamol . With respect to 
    Output:
    
No consistent reports were found for c and i date gene studies of LTMs .
In c and i date gene studies of ICS , the most consistent results were found for rs28364072 in FCER2 .
AND CLINICAL RELEVANCE There is a lack of replication of genetic variants associated with poor ICS or LTM response .
The most consistent results were found for the FCER2 gene [ encoding for a low-affinity IgE receptor ( CD23 ) ] and poor ICS response .