The prevalence of asthma in children has doubled over the past 25 years.1 Two common polymorphisms exist in the adrenoceptor at amino acids 16 (glycine for arginine) and 27 (glutamic acid for glutamine). Both are functionally relevant in cultured cells, with the glycine 16 form of the receptor showing enhanced downregulation and the glutamic acid 27 form showing attenuated downregulation after exposure to agonists.2 The glutamine 27 polymorphism is associated with raised IgE concentrations in families with a history of asthma, and with increased reactivity of the airways in people with asthma.3 4 We measured the prevalence of these polymorphisms in a random population of children to identify their importance in the expression of reported asthma. Subjects, methods, and resultsWe approached children between the ages of 5 and 15 years (mean 10.5 years) and an accompanying parent who were attending the accident and emergency department of the Royal Aberdeen Children's Hospital. Approval from an ethics committee and written consent were obtained from the parents and participating children, and 425 (97%) of 438 agreed to participate. After completing a brief questionnaire each child provided a mouth wash sample (10 ml of boiled distilled water).1 From the resulting suspension of buccal epithelial cells DNA was extracted, and the 2 adrenoceptor polymorphisms were identified using the polymerase chain reaction and an allele specific oligonucleotide assay.3 Frequency tables and Pearson's 2 test were used for bivariate comparisons and logistic regression employed in the multivariate analysis.Complete information including phenotype information on both parents and genotype information in children was available for 410 children with genotyping data in 419. The childhood prevalence of reported asthma (104 out of 425, 24%) was similar to that observed in a recent postal questionnaire study from the same population. 5Thirty nine were arginine 16 homozygotes, 179 were glycine 16 homozygotes, and 201 were heterozygotes. Ninety three were glutamic acid 27 homozygotes, 107 were glutamine 27 homozygotes, and 219 were heterozygotes for the two. The two polymorphisms were in partial linkage disequilibrium. The allelic prevalences of the 2 polymorphisms in this child population were virtually identical with those found in a random sample of adults in Nottingham (unpublished data). Both polymorphisms were in Hardy-Weinburg equilibrium.Genotype at position 16 was not associated with reported asthma. Both homozygosity and heterozygosity for the glutamine 27 polymorphism were associated with reported asthma (table), with a significant association between the presence of this allele and reported asthma ( 2 = 4.38, df = 1, P = 0.04). On logistic regression analysis and taking other known factors into account (sex, maternal asthma, reported hay fever, and eczema) the glutamine 27 allele conferred an independent increased risk of reported asthma (odds ratio 2.18, confidence interval 1.13 to 4.23, P = 0.02). Conversely, homozygosity for the gl...
The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with short- and long-acting beta2-agonists and to evaluate any possible association with genetic polymorphism. Thirty-eight patients with stable mild to moderate asthma and receiving inhaled corticosteroids were randomized in a parallel group, double-blind, double-dummy fashion to receive 2 weeks of treatment with either formoterol (12 microg once daily, 6 microg twice daily or 24 microg twice daily) or terbutaline (500 microg four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expiratory volume in 1.0 s: PD20) was measured at baseline (unprotected) after an initial 1 week run-in without beta2-agonist, and at 1 h after the first and last doses of each treatment. The PD20 values were log-transformed and calculated as change from baseline. Percentage desensitization of log PD20 for first- versus last-dose bronchoprotection was calculated and analysed according to effects of treatment and beta2-adrenoceptor polymorphism at codon 16 or 27. The mean degree of desensitization for bronchoprotection was comparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values were (as microg of methacholine, geometric means+/-S. E.M.): formoterol, 12 microg once daily, 99+/-42 microg; formoterol, 6 microg twice daily, 107+/-44 microg; formoterol, 24 microg twice daily, 108+/-45 microg; terbutaline, 500 microg four times daily, 88+/-37 microg. All patients receiving formoterol, 24 microg twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lower doses of formoterol (12 microg once daily or 6 microg twice daily) showed wider variability in the propensity for protection loss in patients who were heterozygous, in contrast to a more uniform protection loss seen with homozygous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean+/-S.E.M.) for percentage desensitization according to each genotype (pooled treatments): Gly-16, 66+/-11%; Het-16, 53+/-8%; Arg-16, 69+/-18%; Glu-27, 68+/-12%; Het-27, 58+/-8%; Gln-27, 52+/-12%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to short- or long-acting beta2-agonist exposure irrespective of beta2-adrenoceptor polymorphism at codon 16 or 27. Further studies with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol.
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