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Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma.

ABSTRACT: OBJECTIVE:We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control. METHODS:A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult asthma. KEY RESULTS:The results indicated that LTA4H A-9188>G, TNF? G-308>A and IL-4R? A1727>G polymorphisms were significantly associated with the development of difficult asthma in paediatric patients (p<0.001, p = 0.019 and p = 0.037, respectively). Haplotype analysis also revealed two haplotypes (ATA haplotype of IL-4R? A1199>C, IL-4R? T1570>C and IL-4R? A1727>G and CA haplotype of TNF? C-863>A and TNF? G-308>A polymorphisms) which were significantly associated with difficult asthma in children (p = 0.04 and p = 0.018, respectively). CONCLUSIONS AND CLINICAL RELEVANCE:The study revealed multiple SNPs and haplotypes in LTA4H, TNF? and IL4-R? genes which constitute risk factors for the development of difficult asthma in children. Of particular interest is the LTA4H A-9188>G polymorphism which has been reported, for the first time, to have strong association with severe asthma in children. Our results suggest that screening for patients with this genetic marker could help characterise the heterogeneity of responses to leukotriene-modifying medications and, hence, facilitate targeting these therapies to the subset of patients who are most likely to gain benefit.

SUBMITTER: Almomani B

PROVIDER: S-EPMC3616093 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma.

Almomani Basima B Hawwa Ahmed F AF Millership Jeffrey S JS Heaney Liam L Douglas Isabella I McElnay James C JC Shields Michael D MD

PloS one 20130403 4

<h4>Objective</h4>We tested the hypothesis that patients with difficult asthma have an increased frequency of certain genotypes that predispose them to asthma exacerbations and poor asthma control.<h4>Methods</h4>A total of 180 Caucasian children with confirmed asthma diagnosis were selected from two phenotypic groups; difficult (n = 112) versus mild/moderate asthma (n = 68) groups. All patients were screened for 19 polymorphisms in 9 candidate genes to evaluate their association with difficult ...[more]

PMID: 23573270

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Project description:BackgroundTreatment levels required to control asthma vary greatly across a population with asthma. The factors that contribute to variability in treatment requirements of inner-city children have not been fully elucidated.ObjectiveWe sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma.MethodsAsthmatic children aged 6 to 17 years underwent baseline assessment and bimonthly guideline-based management visits over 1 year. Difficult-to-control and easy-to-control asthma were defined as daily therapy with 500 μg of fluticasone or greater with or without a long-acting β-agonist versus 100 μg or less assigned on at least 4 visits. Forty-four baseline variables were used to compare the 2 groups by using univariate analyses and to identify the most relevant features of difficult-to-control asthma by using a variable selection algorithm. Nonlinear seasonal variation in longitudinal measures (symptoms, pulmonary physiology, and exacerbations) was examined by using generalized additive mixed-effects models.ResultsAmong 619 recruited participants, 40.9% had difficult-to-control asthma, 37.5% had easy-to-control asthma, and 21.6% fell into neither group. At baseline, FEV1 bronchodilator responsiveness was the most important characteristic distinguishing difficult-to-control asthma from easy-to-control asthma. Markers of rhinitis severity and atopy were among the other major discriminating features. Over time, difficult-to-control asthma was characterized by high exacerbation rates, particularly in spring and fall; greater daytime and nighttime symptoms, especially in fall and winter; and compromised pulmonary physiology despite ongoing high-dose controller therapy.ConclusionsDespite good adherence, difficult-to-control asthma showed little improvement in symptoms, exacerbations, or pulmonary physiology over the year. In addition to pulmonary physiology measures, rhinitis severity and atopy were associated with high-dose asthma controller therapy requirement.

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.

Dataset Information

Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma.

Publications

Can certain genotypes predispose to poor asthma control in children? A pharmacogenetic study of 9 candidate genes in children with difficult asthma.

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