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，影响全球超过3亿人和2000万美国人。皮质类固醇（CS）是最有效的抗炎药物，用于控制哮喘。然而，据报道，药物反应的个体间差异很大，而个体内的反应是高度可重复的，这表明遗传成分。先前的CS反应的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（小等位基因频率< 0.05），这可能解释了部分缺失的遗传力。我们假设，通过下一代全外显子组测序鉴定出的新编码变体调节了哮喘中的CS反应。本提案概述了一种用于鉴定哮喘患者CS反应相关功能变异的翻译基因组学方法。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）变异。然后，我们将对CS反应进行全面分析，即我们单独测试每个常见变体，但将基因内的所有罕见变体组合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功能

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.