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Despite advances in treatment, asthma continues to be a significant health and economic burden. Although asthma cannot be cured, several drugs, including β2 agonists, corticosteroids, and leukotriene (LT) modifiers, are well tolerated and effective in minimizing symptoms, improving lung function, and preventing exacerbations. However, inter-patient variability in response to asthma drugs limits their effectiveness. It has been estimated that 60-80% of this inter-patient variability may be attributable to genetic variation. LT modifiers, in particular, have been associated with heterogeneity in response. These drugs exert their action by inhibiting the activity of cysteinyl leukotrienes (CysLTs), which are potent bronchoconstrictors and pro-inflammatory agents. Two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting β2 agonist in severe persistent asthma. At least six genes encode key proteins in the LT pathway: arachidonate 5-lipoxygenase (ALOX5), ALOX5 activating protein (ALOX5AP [FLAP]), leukotriene A4 hydrolase (LTA4H), LTC4 synthase (LTC4S), the ATP-binding cassette family member ABCC1 (multidrug resistance protein 1 [MRP1]), and cysteinyl leukotriene receptor 1 (CYSLTR1). Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients. Physio-chemical characteristics make it likely that membrane efflux and uptake transporters mediate the absorption of LTRAs into the systemic circulation following oral administration. Genes that encode efflux and uptake transport proteins harbor many variants that could influence the pharmacokinetics, and particularly the bioavailability, of LTRAs, and could contribute to heterogeneity in response. In the future, large, well designed clinical trials studying the pharmacogenetics of LT modifiers in diverse populations are warranted to determine whether a genetic signature can be developed that will accurately predict which patients will respond. [ABSTRACT FROM AUTHOR]

Our goal was to explore associations between ß 2 adrenergic receptor polymorphisms and markers of asthma severity in African American and Caucasian patients with asthma. Polymorphisms at loci -1023, -654, -47, 46, 79, 491, and 523 were genotyped and haplotypes were imputed in 143 African Americans and 336 Caucasians. C523A genotype associated with percentage of African Americans (but not of Caucasians) having an asthma exacerbation: AA, AC, and CC genotypes were 17, 29, and 40%, respectively ( p = 0.018). Symptom scores, pulmonary function, and rescue inhaler use paralleled exacerbation prevalence. We conclude the 523 A allele modifies asthma severity in African Americans. [ABSTRACT FROM AUTHOR]

Aim Cysteinyl leukotrienes are important pro-inflammatory mediators in the pathogenesis of asthma, while leukotriene C[sub 4] 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 m 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. Conclusion Polymorphisms of leukotriene C[sub 4] synthase did not determine responsiveness, in terms of attenuation of bronchial hyperresponsiveness, to leukotriene receptor antagonists m 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. [ABSTRACT FROM AUTHOR]

Reports a case study which examined the disposition of transplacentally acquired procainamide and its active metabolite in the neonate. Background on the subject; Pharmacokinetic analysis; Results; Discussion.

Abstract Asthma causes enormous suffering and cost for children in the US and around the world [ 1–3 ]. Co-morbid gastroesophageal reflux disease (GERD) makes asthma management more difficult due to increased symptoms. Proton pump inhibitor (PPI) drugs are effective at improving to GERD symptoms, however they have demonstrated only modest and variable effects on asthma control in the setting of co-morbid GERD. Importantly, PPI metabolism and efficacy depend on CYP2C19 genotype. The Genotype Tailored Treatment of Symptomatic Acid Reflux in Children with Uncontrolled Asthma (GenARA) study is a randomized, double-blind, placebo-controlled trial to determine if genotype-tailored PPI dosing improves asthma symptoms among children with inadequately controlled asthma and GERD symptoms. This study has an innovative design to both assess the efficacy of genotype-tailored PPI dosing and perform pharmacokinetic modeling of the oral PPI Lansoprazole. Children ages 6–17 years old with clinician-diagnosed asthma and mild GERD symptoms will submit a saliva sample for CYP2C19 genotyping. Participants will undergo a two-step randomization to: (1) genotype-tailored versus conventional dosing of open-label oral lansoprazole for pharmacokinetic modeling, and (2) genotype-tailored lansoprazole daily versus placebo for 24 weeks to determine the effect of genotype-tailored PPI dosing on asthma control. Measures of asthma control, spirometry, and nasal washes during acute illnesses will be collected at 8-week intervals throughout the study. GenARA will better define the effects of CYP2C19 genotype on the dose response of lansoprazole in children and adolescents and assess if a novel dosing regimen improves GERD and asthma control. [ABSTRACT FROM AUTHOR]

Background: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. Methods: Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts. Results: Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1from baseline in response to montelukast. Conclusions: Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics. [ABSTRACT FROM AUTHOR]

Objective. To determine whether high BMI-percentile is associated with misdiagnosis of asthma among children referred to an asthma specialist. Methods. We queried the electronic records of children 8 to 18 years of age seen by a Nemours pediatric pulmonologist. All visits during a 6-year period with the chief complaint of asthma, or an asthma-like symptom such as wheeze, cough, or dyspnea, were included. We collected spirometry, blood counts, and immunoglobulin E (IgE) if available. We determined whether the child had referring physician-diagnosed asthma, specialist-diagnosed asthma, or both. Specialist-diagnosed asthmatics who met additional objective “gold-standard” criterion were labeled strict-criterion asthma. Results. Prevalence of high BMI-percentile was extremely common in all defined asthma groups, even those meeting strict criteria for diagnosis. Referring physician-diagnosed asthmatics did not have higher rates of obesity, and referring physician-diagnosed asthmatics had objective indicators of asthma that were the same as asthmatics diagnosed by a specialist. There was good diagnostic correlation between referring physicians and asthma specialists that was not affected by BMI. Among specialist-diagnosed asthmatics, increased BMI-percentile associated with significantly reduced forced expiratory volume in 1 second (FEV1), forced expiratory flow during the middle half of the forced vital capacity (FEF25 - 75), and FEV1/forced vital capacity (FVC); and significantly increased total blood leukocytes, neutrophils, and platelets compared to leans. For all 2,258 referrals, the estimated odds ratio of receiving a specialist-diagnosis of asthma increased by 0.4% with each increasing BMI percentile. Conclusions. Referring physicians do not appear to erroneously diagnose children with asthma due to overweight status. Our data confirm that overweight status is extremely high in children with true asthma and likely increases the risk for true asthma. Although these data cannot discern causality, high BMI-percentile is associated with greater airflow obstruction and elevated markers of systemic inflammation that could contribute to underlying mechanisms of asthma. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Proton pump inhibitors (PPIs) are often used in pediatrics to treat common gastrointestinal disorders, and there are growing concerns for infectious adverse events. Because CYP2C19 inactivates PPIs, genetic variants that increase CYP2C19 function may decrease PPI exposure and infections. We tested the hypothesis that CYP2C19 metabolizer phenotypes are associated with infection event rates in children exposed to PPIs. METHODS: This retrospective biorepository cohort study included individuals aged 0 to 36 months at the time of PPI exposure. Respiratory tract and gastrointestinal tract infection events were identified by using International Classification of Diseases codes in the year after the first PPI mention. Variants defining CYP2C19 *2, *3, *4, *8, *9, and *17 were genotyped, and all individuals were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs). Infection rates were compared by using univariate and multivariate analyses. RESULTS: In all, 670 individuals were included (median age 7 months; 44% girls). CYP2C19 NMs (n = 267; 40%) had a higher infection rate than RM/UMs (n = 220; 33%; median 2 vs 1 infections per person per year; P = .03). There was no difference between poor or intermediate (n = 183; 27%) and NMs. In multivariable analysis of NMs and RM/UMs adjusting for age, sex, PPI dose, and comorbidities, CYP2C19 metabolizer status remained a significant risk factor for infection events (odds ratio 0.70 [95% confidence interval 0.50-0.97] for RM/UMs versus NMs). CONCLUSIONS: PPI therapy is associated with higher infection rates in children with normal CYP2C19 function than in those with increased CYP2C19 function, highlighting this adverse effect of PPI therapy and the relevance of CYP2C19 genotypes to PPI therapeutic decisionmaking. [ABSTRACT FROM AUTHOR]

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype‐guided pediatric dosing of PPI medications. Children aged 5–17 years old with gastric‐acid‐related conditions were randomized to receive either conventional dosing of a PPI or genotype‐guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype‐guided dosing arm (P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype‐guided dosing arm. The number of participants who reported an infection was marginally lower in genotype‐guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype‐guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype‐guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI‐associated infections. A future large scale randomized clinical trial of CYP2C19 genotype‐guided pediatric dosing of PPI medications in children is warranted. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Adult obesity is linked to asthma cases and is estimated to lead to 250 000 new cases yearly. Similar incidence and attributable risk (AR) estimates have not been developed for children. We sought to describe the relationship between overweight and obesity and incident asthma in childhood and quantify AR statistics in the United States for overweight and obesity on pediatric asthma. METHODS: The PEDSnet clinical data research network was used to conduct a retrospective cohort study (January 2009-December 2015) to compare asthma incidence among overweight and/or obese versus healthy weight 2- to 17-year-old children. Asthma incidence was defined as ≥2 encounters with a diagnosis of asthma and >1 asthma controller prescription. Stricter diagnostic criteria involved confirmation by spirometry. We used multivariable Poisson regression analyses to estimate incident asthma rates and risk ratios and accepted formulas for ARs. RESULTS: Data from 507 496 children and 19 581 972 encounters were included. The mean participant observation period was 4 years. The adjusted risk for incident asthma was increased among children who were overweight (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.10-1.25) and obese (RR: 1.26; 95% CI: 1.18-1.34). The adjusted risk for spirometry-confirmed asthma was increased among children with obesity (RR: 1.29; 95% CI: 1.16 -1.42). An estimated 23% to 27% of new asthma cases in children with obesity is directly attributable to obesity. In the absence of overweight and obesity, 10% of all cases of asthma would be avoided. CONCLUSIONS: Obesity is a major preventable risk factor for pediatric asthma. [ABSTRACT FROM AUTHOR]

Esophageal pH monitoring remains a primary diagnostic tool for detecting gastroesophageal reflux disease (GERD). GERD that is refractory to proton pump inhibitor (PPI) medications may be related to CYP2C19 variants. Current PPI dosing practices in children do not take into account CYP2C19 allelic variants, which may lead to underdosing and subsequently to a misperception of PPI therapy failure. We hypothesized that pH probe acid exposure outcomes associate with CYP2C19* 17 alleles among children with clinical concern for GERD. We identified a retrospective cohort of 74 children (age range 0.71-17.1 years, mean 8.5, SD 4.6) with stored endoscopic tissue samples and who had also undergone esophageal pH testing while on PPI therapy. These individuals were genotyped for common CYP2C19 alleles and were dichotomized to either CYP2C19*17 allelic carriers without corresponding loss of function alleles as cases vs controls. Associations between pH probe acid exposure outcomes and CYP2C19* 17 alleles were investigated. Compared to controls, children who carry CYP2C19*17 alleles without corresponding loss-of-function alleles demonstrated statistically significant longer times with pH < 4 (76.46 vs 33.47 minutes, P = .03); and higher percent of time with pH < 4.0 (5.71 vs 2.67 minutes, P = .04). These findings remained statistically significant using multiple-regression modeling with test duration, PPI dose, and race as confounding variables. PPI therapy in children with * 17 alleles may be better optimized with CYP2C19 genotype-guided dosing prior to pH probe testing. [ABSTRACT FROM AUTHOR]

When pediatric gastroesophageal reflux disease (GERD) that is refractory to proton pump inhibitor (PPI) medication treatment is identified in clinical practice and anti-reflux surgery (ARS) is being considered, genetic factors related to PPI metabolism by the CYP2C19 enzyme are currently not part of the clinical decision-making process. Our objective was to test the hypothesis that the distribution of the extensive metabolizer (EM) phenotypes among children undergoing ARS after failing PPI therapy would differ compared to controls (children with no history of ARS). We conducted a case-control study between children across the Nemours Health System from 2000 to 2014 who received ARS after failing PPI therapy and a control group comprised of healthy children. Our results demonstrated 2.9% of ARSs vs 20.8% of controls were poor metabolizers (PMs), 55.9% of ARSs vs 49.0% of controls were normal metabolizers (NMs), and 41.2% of ARSs vs 30.2% of controls were EMs; p = 0.035. Next, we performed a multiple-regression model to account for race as a potential confounding variable and the EM group was significantly associated with ARS compared to controls (OR 9.78, CI 1.25-76.55, p < 0.03).Conclusion: Among children with medically refractory GERD despite PPI therapy, carriage of CYP2C19*17 allele corresponding to the EM phenotype was associated with ARS. Prospective comparative personalized medicine effectiveness studies are needed to determine if CYP2C19 genotype-guided dosing improves response to PPI therapy without a corresponding increase in adverse effects in children. What is known: • Anti-reflux surgery (ARS) is one of the most common surgical procedures performed in children for the indication of refractory gastroesophageal reflux disease (GERD). What is new: • Individualizing PPI medication dosing based on CYP2C19 diplotype may avoid GERD treatment failures and reduce the need for anti-reflux surgery (ARS). [ABSTRACT FROM AUTHOR]

Background: A recent study found lower self-reported prevalence of tobacco smoking in a peri-urban area of Lima, Peru than previously reported in urban samples. These regions encompass substantial proportions of Peru's population -- ones at greater risk of disease due to reduced healthcare access -- but have been less often studied. We validate low smoking prevalence with urine cotinine and characterize chronic disease and lung function outcomes between non-, occasional, and daily smokers. Methods: Data are from the CRONICAS Cohort Study, a population-based longitudinal study in four low-resource Peruvian settings, which began in 2010. Of a baseline cohort of 2978 adults, we prospectively followed 2583 (87%) to determine prevalence of chronic illness. Results: In a baseline sub-sample of 382 participants, median adjusted cotinine was 0.0 mcg/mg (IQR 0-0) for both self-reported non-smokers and occasional smokers compared to 172.3 mcg/mg (IQR 0-709.2) for daily smokers. Creatinine-adjusted cotinine validated daily smoking prevalence of 4.7% at a cutoff of 100 mcg/mg. Kappa statistic for daily smoking and creatinine- adjusted cotinine ≥100 mcg/mg was 0.65 (95% CI 0.47, 0.83), indicating substantial agreement. At baseline, we found 3.3% daily and 8.9% occasional smoking by self-report for the full cohort. Follow-up indicated little difference in chronic disease prevalence between groups. Daily smokers trended toward having a greater decline in FVC (-1%; 95% CI -2.9, 0.8) and FEV1 (-1.3%; 95% CI -3.2, 0.6) over 40 months when compared to non-smokers, whereas the decline in lung function for occasional smokers was similar compared to non-smokers (-0.2% FVC; 95% CI -1.5, 1.0) and (0% FEV1; 95% CI -1.3, 1.3). Conclusions: Our data places Peru within a previously-described pattern of smoking found in much of Latin America, favoring occasional over daily smoking and low cigarette consumption. We determine that there are not significant differences between smoking groups concerning chronic disease outcomes. We favor distinguishing between daily and occasional smokers in order to accurately characterize these low-use populations. [ABSTRACT FROM AUTHOR]

Objective C-type natriuretic peptide ( CNP) and its aminoterminal propeptide ( NTpro CNP) are potential biomarkers of recombinant human growth hormone (rh GH) efficacy. The objective of this study was to describe the pharmacodynamics of plasma CNP and NTpro CNP levels in response to rh GH treatment and to identify the optimal time of sampling after starting rh GH. Design This was a prospective, observational study. Subjects were treated with rh GH for 1 year, with blood sampled at regular intervals. Patients Eighteen prepubertal children, eight with low levels of GH on biochemical testing and ten with idiopathic short stature, completed the study. Measurements Blood levels of CNP, NTpro CNP, GH, insulin-like growth factor-I, leptin and bone-specific alkaline phosphatase were measured. Anthropometrics were obtained. Results Plasma levels of both CNP and NTpro CNP reached peak levels 7-28 days after starting rh GH treatment and then declined to intermediate levels through the first year. Plasma NTpro CNP levels after 14 days trended towards a correlation with height velocity after 6 and 12 months of treatment. Unexpectedly, serum GH levels measured 2 and 28 days after starting rh GH correlated strongly with height velocity after 6 and 12 months of treatment. Conclusions This study identified 14 days after starting rh GH treatment as the optimal time for assessing CNP and NTpro CNP levels as biomarkers of rh GH efficacy. Additionally, we identified GH levels as a potential biomarker. Larger, prospective studies are now needed to test the clinical utility of these biomarkers. [ABSTRACT FROM AUTHOR]

Background: Obese children for unknown reasons report greater asthma symptoms. Asthma and obesity both independently associate with gastro-oesophageal reflux symptoms (GORS). Determining if obesity affects the link between GORS and asthma will help elucidate the obese-asthma phenotype.Objective: Extend our previous work to determine the degree of associations between the GORS and asthma phenotype.Methods: We conducted a cross-sectional study of lean (20%-65% body mass index, BMI) and obese (≥95% BMI) children aged 10-17 years old with persistent, early-onset asthma. Participants contributed demographics, GORS and asthma questionnaires and lung function data. We determined associations between weight status, GORS and asthma outcomes using multivariable linear and logistic regression. Findings were replicated in a second well-characterised cohort of asthmatic children.Results: Obese children had seven times higher odds of reporting multiple GORS (OR=7.7, 95% CI 1.9 to 31.0, interaction p value=.004). Asthma symptoms were closely associated with GORS scores in obese patients (r=0.815, p<0.0001) but not in leans (r=0.291, p=0.200; interaction p value=0.003). Higher GORS scores associated with higher FEV1-per cent predicted (p=0.003), lower airway resistance (R10, p=0.025), improved airway reactance (X10, p=0.005) but significantly worse asthma control (Asthma Control Questionnaire, p=0.007). A significant but weaker association between GORS and asthma symptoms was seen in leans compared with obese in the replicate cohort.Conclusion: GORS are more likely to associate with asthma symptoms in obese children. Better lung function among children reporting gastro-oesophageal reflux and asthma symptoms suggests that misattribution of GORS to asthma may be a contributing mechanism to excess asthma symptoms in obese children. [ABSTRACT FROM AUTHOR]

IMPORTANCE Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. objective To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. INTERVENTIONS Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. MAIN OUTCOMES AND MEASURES The primary outcome measure was change in forced expiratory volume in the first second (FEV,) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. RESULTS Mean changes in prebronchodilator FEV, over 24 weeks were 0.03 L (95% Cl, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% Cl, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% Cl, 1.42-2.54] vs soy isoflavones, 2.20 [95% Cl, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% Cl, 2.7-4.1] vs soy isoflavones, 3.0 [95% Cl, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% Cl, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% Cl, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. CONCLUSIONS AND RELEVANCE Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. [ABSTRACT FROM AUTHOR]

Although accurate measures of heritability are required to understand the pharmacogenetic basis of drug treatment response, these are generally not available, as it is unfeasible to give medications to individuals for which treatment is not indicated. Using a polygenic linear mixed modeling approach, we estimated lower bounds on the heritability of asthma and the heritability of two related drug-response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide single nucleotide polymorphism (SNP) data from existing asthma cohorts. Our estimate of the heritability for bronchodilator response is 28.5% (SE 16%, P=0.043) and airway hyperresponsiveness is 51.1% (SE 34%, P=0.064), whereas we estimate asthma genetic liability at 61.5% (SE 16%, P<0.001). Our results agree with the previously published estimates of the heritability of these traits, suggesting that the linear mixed modeling method is useful for computing the heritability of other pharmacogenetic traits. Furthermore, our results indicate that multiple SNP main effects, including SNPs as yet unidentified by genome-wide association study methods, together explain a sizable portion of the heritability of these traits. [ABSTRACT FROM AUTHOR]

Abstract: Uncontrolled asthma is a major cause of hospitalizations and emergency room visits. Factors including obesity, African ancestry and childhood are associated with increased asthma severity. Considering the high morbidity caused by asthma, relatively few classes of drugs exist to control this common disease. Therefore, new therapeutic strategies may be needed to reduce asthma''s impact on public health. Data suggest that a high fat diet that is deficient in omega-3 fatty acids could promote both obesity and excessive inflammation, resulting in greater asthma severity. Small trials with supplemental omega-3 fatty acids have been conducted with encouraging but inconsistent results. The variability in response seen in past trials may be due to the past subjects'' genetics (specifically ALOX5 rs59439148) or their particular asthma phenotypes. Therefore, the “Nutrigenetic response to Omega-3 Fatty acids in Obese Asthmatics (NOOA)” trial is currently underway and was designed as a randomized, double-blind, placebo controlled intervention study to determine if supplemental omega-3 fatty acids improves symptoms among obese adolescents and young adults with uncontrolled asthma. Here we report the design and rationale for the NOOA trial. Participants were given either 3.18g daily of eicosapentaenoic acid and 822mg daily docosahexaenoic acid, or matched control soy oil, for 24weeks. Change in the asthma control questionnaire score was the primary outcome. Secondary outcomes included spirometry, impulse oscillometry, exacerbation rate, airway biomarkers, systemic inflammation, leukotriene biosynthesis and T-lymphocyte function. NOOA may lead to a new therapeutic treatment strategy and greater understanding of the mechanistic role of diet in the pathogenesis of asthma. [Copyright &y& Elsevier]

Bronchodilator response (BDR) is an important asthma phenotype thatmeasures reversibility of airway obstruction by comparing ung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications sed for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under enetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after dministration of a b2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: AMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide olymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting or age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects rom DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. he lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary nalysis, those with rs295137 TT genotype had amedian BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results uggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in aining a better understanding of the biological mechanisms of differential response to b2-agonists through GWAS. [ABSTRACT FROM AUTHOR]

Objective. The relationship between weight status and asthma characteristics in children remains inadequately defined. Very little has been published on the risk of exacerbation, physician perception of severity, and the level controller treatment prescribed to underweight and obese children with asthma in a real-world setting. Methods. We assessed the diagnostic severity, pulmonary function, exacerbation prevalence, and controller treatment level in 10,559 new asthma patients seen at one of four pediatric asthma subspecialty clinics among three BMI groups. Participants were analyzed by body mass index (BMI)-percentile based on Centers for Disease Control & Prevention classification. Multivariable logistic regression models were used to assess the associations between BMI-percentile cohort group and asthma outcomes. Results. Underweight asthmatics were rare (2.5%) relative to obese asthmatics but appeared to have the greatest impairment in forced vital capacity and had the greatest controller treatment burden. Obese asthmatic children made up 26.2% of our cohort and were more likely to have severe disease (odds ratio (OR) 1.40, 95% confidence interval (CI) 1.06-1.85) and airflow obstruction (OR 1.36, 95% CI 1.16-1.59) compared to normal weight asthmatics. Obese asthmatics were not at greater risk for exacerbation (OR 1.41, 95% CI 0.64-3.11) or high treatment burden (OR 1.03, 95% CI 0.83-1.28). Conclusions. Obesity is more common than underweight status among children with asthma. Both underweight and obese children with asthma have worse lung function and asthma-related outcomes compared to similar normal weight children, though the phenotypic characteristics of underweight and obese asthmatics differed considerably. [ABSTRACT FROM AUTHOR]

The article discusses a study on the effectiveness of the proton pump inhibitor (PPI) lansoprazole in asthmatic children without symptoms of gastroesophageal reflux (GER). The Study of Acid Reflux in Children With Asthma was a randomized placebo-controlled clinical trial in the U.S. that treated children with poor asthma control with either lansoprazole or placebo. More respiratory infections or adverse events were observed in children who received lansoprazole under the study. Children with poorly controlled asthma without GER symptoms and using inhaled corticosteriod showed no improvements in symptoms and lung function.

Context: Asymptomatic gastroesophageal reflux (GER) is prevalent in children with asthma. Untreated GER has been postulated to be a cause of inadequate asthma control in children despite inhaled corticosteroid treatment, but it is not known whether treatment with proton pump inhibitors improves asthma control.Objective: To determine whether lansoprazole is effective in reducing asthma symptoms in children without overt GER.Design, Setting, and Participants: The Study of Acid Reflux in Children With Asthma, a randomized, masked, placebo-controlled, parallel clinical trial that compared lansoprazole with placebo in children with poor asthma control who were receiving inhaled corticosteroid treatment. Three hundred six participants enrolled from April 2007 to September 2010 at 19 US academic clinical centers were followed up for 24 weeks. A subgroup had an esophageal pH study before randomization.Intervention: Participating children were randomly assigned to receive either lansoprazole, 15 mg/d if weighing less than 30 kg or 30 mg/d if weighing 30 kg or more (n = 149), or placebo (n = 157).Main Outcome Measures: The primary outcome measure was change in Asthma Control Questionnaire (ACQ) score (range, 0-6; a 0.5-unit change is considered clinically meaningful). Secondary outcome measures included lung function measures, asthma-related quality of life, and episodes of poor asthma control.Results: The mean age was 11 years (SD, 3 years). The mean difference in change (lansoprazole minus placebo) in the ACQ score was 0.2 units (95% CI, 0.0-0.3 units). There were no statistically significant differences in the mean difference in change for the secondary outcomes of forced expiratory volume in the first second (0.0 L; 95% CI, -0.1 to 0.1 L), asthma-related quality of life (-0.1; 95% CI, -0.3 to 0.1), or rate of episodes of poor asthma control (relative risk, 1.2; 95% CI, 0.9-1.5). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole vs placebo was observed for any asthma outcome. Children treated with lansoprazole reported more respiratory infections (relative risk, 1.3 [95% CI, 1.1-1.6]).Conclusion: In this trial of children with poorly controlled asthma without symptoms of GER who were using inhaled corticosteroids, the addition of lansoprazole, compared with placebo, improved neither symptoms nor lung function but was associated with increased adverse events.Trial Registration: clinicaltrials.gov Identifier: NCT00442013. [ABSTRACT FROM AUTHOR]

Background: The relationship between obesity and asthma remains inadequately defined. Studies about how obesity affects asthma control and lung function show conflicting results. Additional focus on the effect of age as a modifier may make clearer the interaction between obesity and asthma phenotype. We sought to use a diverse and well-phenotyped cohort of asthmatic patients to determine how age impacts the relationship between obesity and spirometry, peak flow variability, airflow perception, and asthma control.Methods: The characteristics of 490 patients with mild persistent asthma taken from 2,794 study visits from a prospective trial studying strategies of step-down therapy were included in this post hoc analysis. A longitudinal mixed-effect model was used to determine if age affects the relationship between obesity and asthma characteristics, including spirometry, asthma control, airway pH, and perception of airflow changes.Results: The effect of obesity on asthma outcomes changes with age and gender. Obese 6- to 11-year-old children had the largest reduction in lung function but reported relatively fewer asthma symptoms than did similar nonobese asthmatics. Obese 12- to 17-year-olds showed a trend toward greater airflow obstruction and asthma symptoms compared with nonobese asthmatics. Adults in general displayed few obesity-related alterations in asthma phenotype. Female gender among 12- to 17- and 18- to 44-year-olds was associated with greater obesity-related asthma impairment.Conclusions: Age is a significant effect modifier on the relationship between obesity and asthma phenotype. With increasing age, the influence of obesity on the asthma phenotype is generally reduced. The asthma phenotype may be most impacted by obesity among children and women.Trial Registry: ClinicalTrials.gov; No.: NCT00156819; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

The article presents a cohort study of asthmatic patients aimed at determining how age impacts the relationship between obesity and spirometry, peak flow variability, airflow perception and asthma control. The study reveals that the effect of obesity on asthma outcomes alters with age and gender. The authors also note that the asthma phenotype may be most impacted by obesity among children and women.

Bronchial asthma is a common inflammatory disease caused by the interaction of genetic and environmental factors. Through a genome-wide association study and a replication study consisting of a total of 7,171 individuals with adult asthma (cases) and 27,912 controls in the Japanese population, we identified five loci associated with susceptibility to adult asthma. In addition to the major histocompatibility complex and TSLP-WDR36 loci previously reported, we identified three additional loci: a USP38-GAB1 locus on chromosome 4q31 (combined P = 1.87 × 10?12), a locus on chromosome 10p14 (P = 1.79 × 10?15) and a gene-rich region on chromosome 12q13 (P = 2.33 × 10?13). We observed the most significant association with adult asthma at rs404860 in the major histocompatiblity complex region (P = 4.07 × 10?23), which is close to rs2070600, a SNP previously reported for association with FEV1/FVC in genome-wide association studies for lung function. Our findings offer a better understanding of the genetic contribution to asthma susceptibility. [ABSTRACT FROM AUTHOR]

To (i) determine whether montelukast undergoes carrier-mediated uptake; (ii) classify the carrier protein(s) responsible for uptake; (iii) identify specific transporters that mediate transport of montelukast; and (iv) evaluate whether variation in the gene encoding the transport protein(s) influences the pharmacokinetics and pharmacodynamics of montelukast.In-vitro permeability studies of montelukast are carried out using Caco-2 cell culture, a standard model of human intestinal drug transport. In-vivo plasma concentrations of montelukast in an asthmatic population are determined by high-performance liquid chromatography, and genotyping of transport proteins is by LightTyper analysis.Permeability of montelukast has an activation energy of 13.7±0.7 kcal/mol, consistent with carrier-mediated transport. Permeability is saturable at high concentrations of montelukast and follows Michaelis-Menten kinetics. Permeability is subject to competition by sulfobromophthalein, estrone-3-sulfate, pravastatin, taurocholic acid, and cholic acid (P<0.05, percentage of control: 72±7-86±7) and is inhibited by 5-10% citrus juice (P<0.05, maximal inhibition percentage of control: 31±2). An MDCKII cell line expressing OATP2B1 (coded for by the SLCO2B1 gene) displays significantly increased permeability of montelukast (P<0.05, percentage of control: 140±20). A nonsynonymous polymorphism in SLCO2B1, rs12422149; SLCO2B1 {NM_007256.2}:c.935G>A, associates with significantly reduced plasma concentration in patients measured on the morning after an evening dose (P<0.025, square root mean transformed plasma concentration±SE; c.[935G>A]+[935G]=3±1, c.[935G]+[935G]=7.0±0.9) and differential response as assessed by change in baseline Asthma Symptom Utility Index scores after 1 month of therapy (delta mean Asthma Symptom Utility Index; c.[935G>A]+[935G]=0.02±0.01, P=1.0; c.[935G]+[935G]=1.0±0.3, P<0.0001).Altogether, these observations suggest that the genetics of SLCO2B1 may be an important variable in determining the pharmacokinetics and the pharmacodynamics of montelukast. [ABSTRACT FROM AUTHOR]

Corticotropin-releasing hormone receptor (CRHR)-2 participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short-acting β2-agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma.We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic patients recruited as part of the Childhood Asthma Management Program. Replication was conducted in two Caucasian adult asthma cohorts - a cohort of 427 participants enrolled in a completed clinical trial conducted by Sepracor Inc. (Massachusetts, USA) and a cohort of 152 participants enrolled in the Clinical Trial of Low-Dose Theophylline and Montelukast conducted by the American Lung Association Asthma Clinical Research Centers.Five variants were significantly associated with acute bronchodilator response in at least one cohort (P≤0.05). Variant rs7793837 was associated in Childhood Asthma Management Program and Low-Dose Theophylline and Montelukast (P=0.05 and 0.03, respectively) and haplotype blocks residing at the 5′ end of CRHR2 were associated with response in all three cohorts.We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. Although no single variant was significantly associated in all three cohorts, the findings that variants at the 5′ end of CRHR2 are associated in each of three cohorts strongly suggest that the causative variants reside in this region and its genetic effect, although present, is likely to be weak. [ABSTRACT FROM AUTHOR]

The article highlights a study which determines if montelukast and low-dose theophylline affects serum inflammatory and lipid cardiovascular disease (CVD) risk factors in a recently completed clinical trial in asthmatic patients. Patients on the study were randomized to receive either of the treatments or placebo. Results reveals that asthmatic patient receiving montelukast and low-dose theophylline have lower levels of CVD-associated inflammatory biomarkers and lipid levels.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people. [ABSTRACT FROM AUTHOR]

The relationship between β2-adrenoceptor polymorphisms and bronchoprotective response with long-acting β2-adrenoceptor agonists is unknown. We retrospectively analysed data from six placebo-controlled randomized studies in corticosteroid treated asthmatics where formoterol or salmeterol were administered over a 1–2-week period, with prior 1–2 week washout, assessing the primary end point of methacholine P D20 and adenosine monophosphate P C20, following first and last dose, expressed as doubling dose difference from placebo. There was no significant heterogeneity between the different studies. Patients who had homozygous or heterozygous genotypes containing the arginine-16 polymorphism (Arg16-Arg16 or Arg16-Gly16) had greater bronchoprotective subsensitivity compared with the homozygous glycine-16 genotype (Gly16-Gly16), amounting to a mean doubling dose difference of 1.49 (95% CI 0.50, 2.48), after the last dose. Subsensitivity of response was greater with formoterol than salmeterol after the last dose in all genotypes, especially with the arginine-16 polymorphism, amounting to a doubling dose difference of 3.00 (95% CI 1.01, 4.99) between formoterol and salmeterol. Our retrospective analysis showed that the arginine-16 polymorphism was associated with subsensitivity of response for bronchoprotection, which was greater for formoterol than salmeterol. A prospective study will be required in order to further evaluate these findings, particularly to assess whether these differences are mirrored by exacerbations. [ABSTRACT FROM AUTHOR]