CHILDHOOD ASTHMA: EARLY PREVENTION AND PHARMACOGENETICS

我们的研究小组最近证实，早发性哮喘（3岁以前）在11岁时比晚发性哮喘症状更严重，肺功能缺陷更显著（使用支气管扩张剂不易逆转）。 在儿科哮喘临床研究网络的本申请的项目1中，将评估吸入性皮质类固醇在改变早发性哮喘自然史中的潜在作用。 24-47个月的哮喘高危儿童将接受吸入性皮质类固醇或安慰剂治疗，为期18个月。 将在治疗期结束后立即停用试验药物的1年观察期内评估主要结局变量。 无肿瘤和无肿瘤天数将是主要结局变量。 此外，还将比较两个治疗组中从部分呼气流量容积环获得的最大流量和对冷干燥空气的气道反应。 这些技术已成功地开发了我们的小组用于学龄前儿童。Liggett等人描述了β-肾上腺素能受体基因的遗传变异，我们最近报道了一种这样的多态性（残基16中的甘氨酸/精氨酸）与儿童对沙丁胺醇的反应密切相关。 项目2将评估这些遗传变异对轻度持续性和轻度间歇性哮喘受试者标准化治疗反应的影响。 我们希望发现，携带Gly-16变异基因的患者将需要更多的β激动剂，因此需要更多的控制药物，并需要比携带Arg-16变异基因的患者更多的吸入性皮质类固醇。我们的团队是唯一有资格为PACRN做出贡献的团队。 我们在儿童哮喘的长期临床和流行病学研究方面拥有丰富的经验，尤其是在婴儿和学龄前儿童中。 我们还与社区卫生保健提供者建立了密切的合作关系，特别是那些参与图森西班牙裔社区哮喘初级保健的人。 最后，我们在哮喘的遗传学和药物遗传学方面有一个非常活跃的项目，这可能对PACRN的长期目标非常重要。

Our group has recently demonstrated that early onset asthma (before age 3) is associated with more severe symptoms and more significant deficits in lung function (not readily reversible with bronchodilators) at age 11 than late onset asthma. In Project 1 of this application to the Pediatric Asthma Clinical Research Network, the potential role of inhaled corticosteroids in modifying the natural history of early onset asthma will be assessed. Children at high risk for asthma aged 24-47 months will be treated with either inhaled corticosteroids or placebo for a period of 18 months. The main outcome variables will be assessed during a one year observation period off trial drug immediately following the treatment phase. Number of symptom-free and controller-free days will be the main outcome variable. In addition, maximal flows obtained from partial expiratory flow volume loops and airway responses to cold dry air will also be compared in both treatment groups. These techniques have been successfully developed by our group for use in pre-school children. Genetic variants in the beta-adrenergic receptor gene have been described by Liggett et al, and we recently reported that one such polymorphism (glycine/arginine in residue 16) was strongly associated with response to albuterol in children. Project 2 will assess the influence of these genetic variants on response to standardized therapy among subjects with mild persistent and mild intermittent asthma. We expect to find that carriers of the Gly-16 variant of this gene will require more beta agonist and hence receive more control medication and require more inhaled corticosteroids than carriers of the Arg-16 variant. Our group is uniquely qualified to contribute to PACRN. We have a long experience in long-term clinical and epidemiological studies of childhood asthma, especially among infants and pre-schoolers. We have also established strong collaborative links with community health care providers especially those involved in the primary care of asthma among our Hispanic community in Tucson. Finally, we have a very active program in the genetics and pharmacogenetics of asthma that may prove very important for the long-term objectives of PACRN.