Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept.
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ABSTRACT:
SUBMITTER: Sordillo JE
PROVIDER: S-EPMC8073919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR).We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 microg/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population.The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n = 422) and 0.60 (n = 475) and 0.63 (n = 235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations.Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.
| S-EPMC3654515 | biostudies-literature
Project description:RationaleStress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR).ObjectivesTo examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR and non-PR children with asthma.MethodsThis was a cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms, and maternal stress using the Perceived Stress Scale. Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke, and use of inhaled corticosteroids.Measurements and main resultsHigh child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, Checklist of Children's Distress Symptoms) and whose mothers had high stress (upper quartile, Perceived Stress Scale) had a BDR that was 10.2% (95% confidence interval, 6.1-14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This single-nucleotide polymorphism is associated with reduced expression of the gene for the β2-adrenergic receptor (ADRB2) in CD4(+) lymphocytes of subjects with asthma, and it affects brain connectivity of the amygdala and the insula (a biomarker of anxiety).ConclusionsHigh child stress and an ADCYAP1R1 single-nucleotide polymorphism are associated with reduced BDR in children with asthma. This is likely caused by down-regulation of ADRB2 in highly stressed children.
| S-EPMC4511425 | biostudies-literature
Project description:BackgroundOur objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP).MethodsWe performed a cross-sectional analysis evaluating children ages 6 to 17 years with nonsevere asthma (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 µg of albuterol to determine reversibility (≥12% increase in FEV1 ). Participants were then given escalating doses up to 720 µg of albuterol to determine their maximum reversibility.ResultsWe evaluated 230 children (n = 129 SA, n = 101 NSA) from five centers across the United States in the SARP I and II cohorts. SA (odds ratio [OR], 2.08, 95% confidence interval [CI], 1.05-4.13), second-hand smoke exposure (OR, 2.81, 95%CI, 1.23-6.43), and fractional exhaled nitric oxide (FeNO; OR, 1.97, 95%CI, 1.35-2.87) were associated with increased odds of airway reversibility after maximal bronchodilation, while higher prebronchodilator (BD) FEV1 % predicted (OR, 0.91, 95%CI, 0.88-0.94) was associated with decreased odds. In an analysis using the SARP III cohort (n = 186), blood neutrophils, immunoglobulin E (IgE), and FEV1 % predicted were significantly associated with BD reversibility. In addition, children with BD response have greater healthcare utilization. BD reversibility was associated with reduced lung function at enrollment and 1-year follow-up though less decline in lung function over 1 year compared to those without reversibility.ConclusionsLung function, that is FEV1 % predicted, is a predictor of BD response in children with asthma. Additionally, smoke exposure, higher FeNO or IgE level, and low peripheral blood neutrophils are associated with a greater likelihood of BD reversibility. BD response can identify a phenotype of pediatric asthma associated with low lung function and poor asthma control.
| S-EPMC7015037 | biostudies-literature
Project description: Not available
| S-EPMC7250728 | biostudies-literature
Project description:RationaleAlbuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.ObjectivesTo identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.MethodsWe performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.Measurements and main resultsWe identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10-7) and suggestive (P < 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.ConclusionsThe lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.
| S-EPMC6006403 | biostudies-literature
Project description:BACKGROUND:This study evaluates a novel bronchodilator, S1226, for its efficacy in reversing allergen-induced bronchoconstriction in subjects with mild, allergic asthma. S1226 is a new class of bronchodilator that is an aerosol/vapor/gas mixture combining pharmacological and biophysical principles for a novel mode of action. It contains a potent bronchodilator gas (carbon dioxide or CO2) and nebulized perflubron (a synthetic surfactant possessing mucolytic properties). It has demonstrated rapid reversal of allergen-induced bronchoconstriction in an ovine study model. METHODS:This was a phase IIa proof-of-concept, placebo-controlled, randomized, double-blind, crossover single-dose clinical trial to evaluate the safety, tolerability, and efficacy of S1226 (8% CO2) administered by nebulization following an allergen-induced early asthmatic response in 12 subjects with mild, allergic asthma. Primary safety endpoints were adverse events, vital signs, pulse oximetry, and spirometry. Efficacy endpoints included bronchodilator response (measured as the forced expiratory volume in 1 s or FEV1) over time, the area under the curve of FEV1 for the early asthmatic response over time, and achievement of responder status, defined as a 12% improvement after the allergen challenge. RESULTS:No significant safety issues were observed. All adverse events were non-serious, mild, and transient. There was a statistically significant decrease in peripheral blood oxygenation levels over time in the placebo group following allergen inhalation, whereas blood oxygenation was maintained at normal levels in the S1226-treated subjects (P?=?0.028). This effect was greatest 5 min after start of treatment (P?<?0.001). The recovery rate was faster but not significantly so (P?=?0.272) for S1226 compared to the placebo at earlier time points (5, 10, and 15 min), as assessed by ?12% reversal of FEV1. The recovery of FEV1 over time was significantly greater (P?=?0.04) with S1226 compared to the placebo. CONCLUSIONS:S1226 was safe, tolerated well, and provided bronchodilation and improved blood oxygenation in subjects with mild atopic asthma following allergen-induced bronchoconstriction. Additional studies to optimize the therapeutic response are indicated. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02334553 . Registered on 12 November 2014.
| S-EPMC6006836 | biostudies-literature
Project description:BACKGROUND:There is few objective, clinically feasible and inexpensive test for diagnosing childhood asthma. We want to find an ideal way to solve it. METHODS:The control group was 301 non-asthmatic children, and the asthma group was 286 asthmatic children. The asthmatic children were divided into three groups according to the severity of their disease. Pre- and post-bronchodilator spirometer tests were performed, and the main spirometer parameters were compared. The bronchodilator response (BDR) [BDR is used to determine the reversibility of airway obstruction by measuring the changes of forced expiratory volume in the first second (FEV1) before and after inhalation of bronchodilators] was then determined, and the optimal threshold of BDR for diagnosing childhood asthma was found. RESULTS:301 non-asthmatic children and 286 asthmatic children participated in the study, the demographics were similar. FEV1 for pre-bronchodilator of asthmatic children was significantly lower than that of non-asthmatic children (P???0.01). BDR of non-asthmatic children was 3.30?±?3.85%. BDR of asthmatic children was 9.45?±?9.15%. There was no significant difference in BDR for patients with different severities of asthma within the group. BDR had no statistical correlation with gender, age, height, weight in neither non-asthmatic children nor asthmatic children. On the receiver-operating characteristic curve, a BDR threshold of ??7.5% offered an optimal balance in asthma diagnosis with a sensitivity rate of 50.7% and specificity rate of 87.7%. Meanwhile, with a BDR threshold of ??12%, the sensitivity rate was 28.7% and the specificity rate was 96.3%. CONCLUSION:A BDR threshold of ??7.5% has more value in childhood asthma diagnosis as compared to ??12%.
| S-EPMC6872507 | biostudies-literature
Project description:Background: Asthma is common chronic inflammatory disease of the airways with a heterogenous clinical presentation. Individual differences in asthma susceptibility remain poorly understood, although genetics is thought to play a major role. Aim: To build a polygenic risk score (PRS) for asthma and determine whether predictive genetic variants can be epigenomically linked to specific pathophysiological mechanisms. Methods: PRSs were constructed using data from genome-wide association studies and performance was validated using data generated in the Rotterdam Study, a Dutch prospective cohort of 14,926 individuals. Outcomes used were asthma, childhood-onset asthma, adulthood-onset asthma, eosinophilic asthma and exacerbations. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from 14 primary cell types, including lung epithelial cells and T lymphocytes was used for epigenomic PRS partitioning. Results: All PRSs successfully predicted risk to develop asthma and related outcomes, with the strongest predictive power (2.42 odds ratios per PRS standard deviation, area under the curve of 0.736) achieved for childhood-onset asthma. PRSs allowed for stratification of the Rotterdam Study cohort into groups at low or high risk to develop asthma. PRS partitioning using genome-wide epigenomic profiles identified 5 clusters of variants within gene regulatory regions linked to specific asthma-relevant cells, genes and biological pathways. Conclusions: PRSs can predict whether individuals in a Dutch cohort developed asthma and asthma-related phenotypes, which is most effective for childhood-onset asthma. Importantly, we show that PRS partitioning based on epigenomics data dissects a genetic risk score into blocks of regulatory variants with differential predictive power, which likely represent distinct genetically driven disease pathways. These findings have potential implications for personalized risk mitigation and treatment strategies.
2024-07-03 | GSE245569 | GEO
Project description:BACKGROUND:Pharmacogenetic testing may change clinical medicine by allowing clinicians to tailor medications based on a patient's genetic makeup, however, these tests must first be validated in large, real-life populations of subjects that include children. A dearth of knowledge exists for whether pediatric populations are as willing as adult populations to provide samples for such studies. OBJECTIVE:(1) To assess whether pediatric and adult patients with persistent asthma are willing to provide specimens for DNA extraction and genetic studies. (2) To assess whether patients' willingness to provide blood as compared to buccal smear specimens differ. METHODS:Of 644 patients ages 4-38 years who had three or more prescription fills for inhaled corticosteroids in one year, 60% (385) were randomized to the blood specimen group and 40% (259) were randomized to the buccal smear group in order to study acceptance of different biospecimen collection methods. Research assistants contacted subjects to obtain consent, perform a phone survey, and request a specimen. RESULTS:There were no baseline differences between subjects randomized to the blood specimen group versus buccal smear group with respect to age, gender, or number of dispensings of inhaled corticosteroids. Of 259 subjects in the buccal smear group, 30% (78) provided samples, and of 385 subjects in the blood specimen group, 16% (60) provided samples. Subjects randomized to the buccal smear group were more likely to provide specimens for genetic study compared to subjects randomized to the blood specimen group (RR 1.21; 95% CI 1.10 - 1.32), even after adjusting for age. Pediatric subjects were more likely to provide specimens for genetic study than adult subjects with 23% (113) of pediatric subjects providing samples and 15% (25) of adult subjects providing samples (p=0.03). CONCLUSION:Children with asthma are as likely to participate in genetic studies as adults. Both children and adult subjects are more likely to provide buccal smear specimens rather than blood specimens for genetic study.
| S-EPMC3614400 | biostudies-literature
Project description:BackgroundThe bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood.ObjectivesWe sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts.MethodsCases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program. Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs.ResultsA total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%). Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%).ConclusionsOur findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
| S-EPMC3759549 | biostudies-literature