CHILDHOOD ASTHMA: EARLY PREVENTION AND PHARMACOGENETICS

我们的研究小组最近证明，早发性哮喘（3岁之前）与11岁时更严重的症状和更显著的肺功能缺陷（不容易用支气管扩张剂逆转）相关。本项目的项目1是向儿童哮喘临床研究网络申请，将评估吸入皮质类固醇在改变早发性哮喘自然史方面的潜在作用。24-47个月的哮喘高危儿童将接受为期18个月的吸入皮质类固醇或安慰剂治疗。主要结果变量将在治疗阶段结束后立即停止试验的一年观察期进行评估。无症状和无控制器天数将是主要的结局变量。此外，还将比较两个治疗组中由部分呼气流量容积循环获得的最大流量和气道对冷干燥空气的反应。我们小组已经成功地开发了这些技术，用于学龄前儿童。Liggett等人已经描述了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将评估这些基因变异对轻度持续性和轻度间歇性哮喘受试者对标准化治疗反应的影响。我们期望发现该基因Gly-16变体的携带者比Arg-16变体的携带者需要更多的β受体激动剂，因此接受更多的控制药物，并需要更多的吸入皮质类固醇。我们的团队是唯一有资格为PACRN做出贡献的。我们在儿童哮喘的长期临床和流行病学研究方面有着长期的经验，特别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强有力的合作关系，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.