Rare and Common Pharmacogenetic Determinants of Corticosteroid Response in Asthma

描述（由申请人提供）：哮喘是一种慢性呼吸道疾病，影响全球3亿多人和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，已经报告了药物应答的显著个体间变异性，而个体内应答具有高度可重复性，表明存在遗传成分。以前的CS反应药物遗传学研究主要集中在常见的遗传多态性上，罕见变异的代表性较差（次要等位基因频率< 0.05），这可能解释了部分缺失的遗传性。我们假设，新的编码变异，通过下一代测序的整个外显子组确定，调节哮喘的CS反应。该提案概述了一种翻译基因组学方法，用于识别哮喘患者中与CS反应相关的功能变体。首先，我们将从200名哮喘患者的外显子组中识别所有编码（非同义和剪接）变体。然后，我们将对CS反应进行全面分析，从而单独测试每个常见变异，但将基因内的所有罕见变异分组在一起，以确定它们的集体效应。然后，我们建议测试多达三个的功能 相关的编码变体，在细胞模型中进行体外实验。这些发现将提高我们对哮喘CS反应变异性的理解，具有潜在的更广泛的意义，因为这类药物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疗的重要一步，通过确定新的基因组位点影响CS反应，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.