Rare and Common Pharmacogenetic Determinants of Corticosteroid Response in Asthma

描述(申请人提供)：哮喘是一种慢性呼吸道疾病，影响全球超过3亿人和2000万美国人。皮质类固醇(CS)是用于控制哮喘的最有效的抗炎药物。然而，据报道，药物反应的个体间差异很大，而个体内的反应具有高度的重复性，这表明这是一个遗传因素。以前对CS反应的药物遗传学研究主要集中在常见的遗传多态上，稀有变异的代表性很差(次要等位基因频率和0.05)，这可能解释了部分缺失的遗传性。我们假设，通过下一代整个外显子组测序确定的新的编码变体调节哮喘的CS反应。这项建议概述了一种翻译基因组学方法，用于识别与哮喘患者CS反应相关的功能变异。首先，我们将从200名哮喘患者的外显子中识别所有的编码变体(非同义和剪接)。然后，我们将对CS反应进行全面的分析，我们分别测试每个常见的变体，但将一个基因内的所有罕见变体分组在一起，以确定它们的集体效应。然后，我们建议测试最多三个 在细胞模型中使用体外实验的相关编码变体。这些发现将提高我们对哮喘中CS反应变异性的理解，具有潜在的更广泛的影响，因为这类药物被用于治疗其他免疫疾病，如类风湿性关节炎和肾上腺疾病。这项研究将作为个性化医学的重要一步，通过识别影响CS反应的新的基因组位点，最终目标是促进基于基因组的预后测试的发展。

DESCRIPTION (provided by applicant): Asthma is a chronic respiratory disease that affects over 300 million individuals worldwide and 20 million Americans. Corticosteroids (CS) are the most potent, anti-inflammatory drugs used for the control of asthma. However, substantial inter-individual variability in drug response has been reported, whereas the intra- individual response was highly repeatable, suggesting a genetic component. Previous pharmacogenetic studies of CS response focused primarily on common genetic polymorphisms, with poor representation of rare variants (minor allele frequency < 0.05), which likely explain part of the missing heritabilit. We hypothesize that novel coding variants, identified through next-generation sequencing of whole exomes, modulate CS response in asthma. This proposal outlines a translational genomics approach for identifying functional variants associated with CS response in asthma patients. First, we will identify all coding (non-synonymous and splice) variants from the exomes of 200 asthma patients. Then, we will perform a comprehensive analysis of CS response whereby we test each common variant individually but group all rare variants within a gene together to determine their collective effect. Then, we propose to test the function of up to three associated coding variants using in vitro experiments in cellular models. These findings will improve our understanding of CS response variability in asthma, with potentially wider implications as this class of medications is used to treat other immune diseases such as rheumatoid arthritis and adrenal disorders. This investigation will serve as an important step in personalized medicine by identifying novel genomic loci influencing CS response with the ultimate goal of facilitating the development of genomic-based prognostic tests.