Project 2: Novel Risk Factors and Precision Medicine for Gout Flares

项目 2：痛风发作的新危险因素和精准医学

• 批准号: 10263205
• 负责人: HYON K CHOI
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263205
• 关键词: ABCG2 gene; Address; Adult; Affect; Alcohol consumption; Allopurinol; Arthritis; Boston; Caring; Cessation of life; Chronic Kidney Failure; Clinical; Coffee; Data; Databases; Diet; Diuretics; Fibrinogen; Flare; Fructose; Genes; Genetic; Genomics; Goals; Gout; Guidelines; High Prevalence; Hypertension; Hyperuricemia; IGF1R gene; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; Intake; Intervention; Investigation; Life Style; Measures; Metabolism; PRKAG2 gene; Pain; Pathogenesis; Patient Education; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Prevalence; Purines; Race; Recurrence; Registries; Research; Research Design; Rheumatology; Risk; Risk Factors; Role; Series; Serum; Subgroup; Targeted Research; Tea; Therapeutic; Time; Translating; Translational Research; Urate; Variant; biobank; clinical efficacy; clinical practice; cohort; comorbidity; cost effective; dietary; evidence base; experience; genome wide association study; innovation; modifiable risk; novel; personalized approach; precision medicine; premature; risk variant; soft drink; sugar; sweetened beverage

PROJECT SUMMARY Gout is a common and excruciatingly painful inflammatory arthritis associated with hyperuricemia. The prevalence of gout has increased over the past few decades to 3.9% of US adults (8.3 million individuals), which is further complicated by a high level of comorbidities (CoRT theme, including chronic kidney disease (CKD)) and their sequelae (e.g., premature death). Despite our understanding of gout's pathogenesis and available medications, gout management remains suboptimal with recurrent attacks occurring frequently, and there is a clear need to broaden the evidence-based and personalized precision approach to gout care. Our previous Boston Online Gout Study successfully provided the relevant evidence about the role of traditionally purported risk factors for gout flares in pre-existing gout patients, which was endorsed by the latest ACR gout guidelines. However, evidence for purported novel common modifiable risk factors as well as genetic and other key attributes, which are essential for precision gout care, are lacking. To fill this key evidence gap, we will expand our successful platform of the Boston Online Gout Study by following 800 gout patients from the Partners Biobank cohort (N >75,000) and 200 black gout patients from the UAB Rheumatology Arthritis Database and Registry over the course of 1 year. We will first examine novel common modifiable factors (i.e., sugar-sweetened beverages, coffee, and tea) for the risk of gout flares (Aim 1). Furthermore, we will translate recent genomic research data towards precision medicine in gout care for both lifestyle and pharmacologic interventions. Specifically, we will examine the purported influence of urate genes involved in sugar transport (SLC2A9) and metabolism genes (GCKR, IGF1R, and INHBB) on the impact of key risk factors for gout flares (Aim 2). We will also examine the purported impact of the ABCG2 variant (Q141K) and PRKAG2 variant (which encodes the gamma chain of AMPK (a master regulator of gouty inflammation)) on allopurinol's clinical efficacy for gout flares, as well as the purported role of the SLC2A9 variant on diuretic-induced gout flares (Aim 3). Finally, we will examine the role of other key attributes (i.e., race (black) and CKD status (stage 3 or higher)) on the impact of key triggers of gout flares among gout patients to further precision gout care (Aim 4). These aims address novel, common risk factors, gene-environmental interactions, pharmacogenomics, and race/CKD impact, all of which can be readily translated into clinical practice to optimize gout care. Further, the innovative and cost-effective study design leverages our group's extensive gout research experience and provides key research translation for precision medicine in gout. This project will have an important positive impact on millions of gout patients by filling key evidence gaps on modifiable factors and relevant subgroups at risk for gout flares.

项目摘要 痛风是一种与高尿酸血症相关的常见且令人难以置信的疼痛炎症性关节炎。这 在过去的几十年中，痛风的患病率增加到美国成年人的3.9％（830万个人）， 高水平的合并症（Cort主题，包括慢性肾脏疾病）更加复杂 （CKD））及其后遗症（例如，死亡过早）。尽管我们了解了痛风的发病机理和 可用的药物，痛风管理保持不佳，经常发生反复攻击，并且 显然需要扩大基于证据和个性化的痛风护理的精确方法。我们的 以前的波士顿在线痛风研究成功地提供了有关传统作用的相关证据 曾曾有过痛风患者中痛风耀斑的危险因素，这是最新的ACR痛风的认可 指南。但是，据称是新型常见的可修改风险因素以及遗传和遗传的证据 缺乏对精确痛风护理至关重要的其他关键属性。填写这个关键证据 差距，我们将通过以下800名痛风患者来扩大波士顿在线痛风研究的成功平台 来自Partners Biobank队列（n> 75,000）和200名来自UAB风湿关节炎的黑痛风患者 在1年的过程中数据库和注册表。我们将首先检查新颖的常见可修改因素（即 糖甜的饮料，咖啡和茶）出于痛风的风险（AIM 1）。此外，我们将翻译 最新的基因组研究数据，用于对生活方式和生活方式的痛风护理中的精确医学 药理学干预措施。具体而言，我们将研究涉及的尿酸盐基因的影响 糖运输（SLC2A9）和代谢基因（GCKR，IGF1R和INHBB）对关键危险因素的影响 用于痛风耀斑（AIM 2）。我们还将研究ABCG2变体（Q141K）和PRKAG2的所谓影响 在别嘌呤醇的上 痛风耀斑的临床功效，以及SLC2A9变体在利尿剂诱导的痛风上的作用 耀斑（目标3）。最后，我们将研究其他关键属性的作用（即种族（黑色）和CKD状态 （第3阶段或更高））关于痛风患者痛风耀斑关键触发器的影响，以进一步精确痛风护理 （目标4）。这些目的涉及新颖的常见危险因素，基因 - 环境相互作用， 药物基因组学和种族/CKD撞击，所有这些都可以轻松地转化为临床实践 优化痛风护理。此外，创新且具有成本效益的研究设计利用了我们小组的广泛 痛风研究经验，并为痛风提供了精确医学的关键研究翻译。这个项目 通过填补可修改的关键证据差距，将对数百万的痛风患者产生重要的积极影响 因素和相关亚组有痛风耀斑的风险。