Pharmacogenomic and Metabolic Optimization of Glucocorticoid Therapy for Asthma

摘要： 哮喘和其他疾病的个人化糖皮质激素(GC)治疗如果有针对性，可能成为现实 遗传标记与个体患者对治疗的反应密切相关。我们的研究已经 细胞色素P450 3A4和细胞色素P450 3A5的2个失活单核苷酸多态(SNPs) 这些酶显示哮喘儿童对吸入GCs的反应有所改善。我们提出了这些SNPs 缓慢的呼吸道和全身清除吸入的GC，延长其抗炎作用，从而提供 卓越的哮喘控制能力。这些临床观察进一步得到了GC代谢的体外研究的支持 通过细胞色素P3A酶。基于这些令人兴奋的发现，我们假设使用GC控制哮喘 可以通过使用患者的CYP3A基因图谱和相关基因来指导患者选择 一个合适的GC，它的剂量，也许还有其他辅助疗法。我们建议通过以下方式来检验这一假设 以下任务：1)确定额外的基因型：吸入GC疗效：儿童哮喘控制相关性 哮喘；2)对患者进行药代动力学研究，以测量氟替卡松的全身清除量 丙酸(FP)和二丙酸倍氯米松(BDP)与CYP3A4和CYP3A5基因相关 具体而言，分别是CYP3A4*22和CYP3A5*3对野生型的影响；以及 证明用药控制哮喘症状之间的纵向联系：基因组合 使用一种新型的患者监测系统--电子哮喘跟踪器(e-AT)来测量用药情况 依从性，结合肺功能的生理评估，这在监测时是必不可少的 对药物治疗的持续反应。本研究的总体目标是进一步了解生物化学。 哮喘对照中CYP3A4*22：FP与CYP3A5*3：BDP基因型的关系及临床意义 关联并扩展这些观察结果，以解释影响GC的其他关联遗传变异 新陈代谢、疗效和哮喘护理。吸入型糖皮质激素(GCs)是治疗以下疾病的主要药物 控制哮喘。然而，GC无法控制高达50%的人的哮喘症状。因此，至关重要的是 了解限制疗效的因素，以指导选择最佳治疗方案，以最大限度地提高效益和 降低医疗成本。我们希望这些研究能解释我们在3A4和3A5上的发现，并揭示新的 哮喘控制与“细胞色素P3A酶系统”各成分GCs和SNPs的关系 它可以作为使用GC改善哮喘护理的框架。

Abstract: Personalized glucocorticoid (GC) therapy for asthma and other diseases could become a reality if specific genetic markers were strongly associated with an individual patient's response to therapy. Our studies have identified 2 inactivating single nucleotide polymorphisms (SNPs) in Cytochrome P450 3A4 and CYP3A5 enzymes that show improved responses to inhaled GCs among children with asthma. We propose these SNPs slow airway and systemic clearance of inhaled GCs, prolonging their anti-inflammatory effects, thereby providing superior asthma control. These clinical observations are further supported by in vitro studies of GC metabolism by the CYP3A enzymes. Building upon these exciting findings, we hypothesize that asthma control with GCs can be improved by using a patient's genetic profile for CYP3A and related genes to guide both the selection of an appropriate GC, its dose, and perhaps other adjuvant therapies. We propose to test this hypothesis through the following tasks: 1) Identify additional genotype:inhaled GC efficacy:asthma control correlations in children with asthma; 2) conduct a pharmacokinetic study with patients to measure systemic clearance of fluticasone propionate (FP) and beclomethasone dipropionate (BDP), relative to CYP3A4 and CYP3A5 genotype - specifically the effects of CYP3A4*22 and CYP3A5*3 versus wild-type genotypes, respectively; and 3) demonstrate longitudinal associations between asthma symptom control for medication:genotype combinations using a novel patient monitoring system, the electronic Asthma Tracker (e-AT), to measure medication compliance, combined with physiologic assessments of pulmonary function, which are essential when monitoring sustained responses to drug therapy. The overall objective of this study is to further understand the biochemical relationship and clinical significance of the CYP3A4*22:FP and CYP3A5*3:BDP genotype:asthma control associations and expand these observations to account for other associated genetic variations that impact GC metabolism, efficacy, and asthma care. Inhaled glucocorticoids (GCs) are the primary medications prescribed to control asthma. However, GCs fail to control asthma symptoms in up to 50% of people. Thus, it is critical to understand factors that limit efficacy in order to guide the selection of the best treatment to maximize benefit and reduce healthcare costs. We expect these studies to explain our findings on CYP3A4 and 3A5 and to reveal new relationships between asthma control, GCs and SNPs in various components of the “CYP3A enzyme system” which can be used as a framework to improve asthma care using GCs.