GENOMICS AND PHARMACOGENOMICS OF SYMPTOMS IN ASTHMA

描述（由申请人提供）：哮喘影响全球超过3亿人。哮喘症状与整体生活质量密切相关；持续症状导致哮喘控制不良，导致不成比例的发病率和费用。全基因组关联研究已广泛应用于哮喘易感性和哮喘肺功能的研究，但尚未系统地应用于哮喘自我报告症状的研究。该项目的主要目标是通过全基因组关联研究来彻底研究哮喘症状的遗传起源。为了实现这一目标，我们指定了三个相关但独立的目标。第一个目标是评估超过50万个遗传标记与临床试验或临床队列登记时报告的症状的关联数据。具有最强关联证据的标记将在独立的临床队列中进行重复性测试。第二个目的是了解症状对药物治疗反应的遗传基础（药物遗传学）。而不是分析基线症状，症状的变化作为吸入皮质类固醇药物的反应将是该目的的主要结果表型，这也将使用全基因组关联测试和复制方法。我们的最终目标是建立一个模型，利用基因型和表型特征，包括人口统计学、社会心理和行为因素，来预测谁在哮喘中出现持续症状的风险最大。数十到数百个遗传标记将用于开发这些预测性测试，这些测试将针对持续症状和症状的治疗反应进行制定和验证。我们相信这些发现将揭示哮喘症状的遗传基础，并导致新的干预措施来预测和减轻这一主要的卫生保健问题。

DESCRIPTION (provided by applicant): Asthma affects over 300 million individuals worldwide. Asthma symptoms are tightly correlated with overall quality of life; persistent symptoms resulting in poor asthma control leads to disproportionate morbidity and cost. Genome-wide association studies have been extensively applied to the study of asthma susceptibility and lung function in asthma, but have yet to be applied in a systematic fashion to studies of self-reported symptoms in asthma. The major goal of this project is to thoroughly investigate the genetic origins of asthma symptoms via genome-wide association study. To accomplish this, we have specified three related but independent aims. The first aim evaluates data from over 500,000 genetic markers for their association with symptoms as reported at the time of enrollment into a clinical trial or clinical cohort. The markers with the strongest evidence for association will be tested for replication in independent clinical cohorts. The second aim seeks to understand the genetic basis for response of symptoms to drug treatment (pharmacogenetics). Instead of analyzing baseline symptoms, the change in symptoms as a response to inhaled corticosteroid medications will be the primary outcome phenotype for this aim, which will also use genome-wide association testing and replication methods. Our final aim will be to develop a model, using both genotype and phenotypic characteristics, including demographic, psychosocial, and behavioral factors, to predict who is at greatest risk of developing persistent symptoms in asthma. Dozens to hundreds of genetic markers will be used to develop these predictive tests, which will be formulated and validated for both persistent symptoms and treatment response of symptoms. We believe that these findings will uncover the genetic basis for symptoms in asthma and lead to novel interventions to predict and alleviate this major health care problem. PUBLIC HEALTH RELEVANCE: Asthma affects an estimated 300 million individuals worldwide and accounts for approximately $20 billion in direct health care costs in the United States annually, with a disproportionate proportion of those costs allocated to uncontrolled, persistently symptomatic individuals. The identification of genetic variants that can be used as the basis of a prognostic test to predict which individuals will or will not demonstrate symptoms and respond to therapy has the potential to substantially decrease both morbidity and financial burden related to asthma as well as to improve the overall quality of life for subjects with asthma and their care providers.