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.

项目概要 痛风是一种常见且极其疼痛的炎症性关节炎，与高尿酸血症相关。这 在过去的几十年里，美国成年人（830 万人）的痛风患病率已上升至 3.9%， 高水平的合并症（CoRT 主题，包括慢性肾病 （CKD））及其后遗症（例如过早死亡）。尽管我们了解痛风的发病机制并 可用药物治疗，痛风治疗仍不理想，经常反复发作，并且 显然需要扩大痛风护理的循证和个性化精确方法。我们的 先前的波士顿在线痛风研究成功地提供了传统痛风作用的相关证据 据称，已有痛风患者出现痛风发作的危险因素，这一点得到了最新 ACR 痛风研究的认可 指导方针。然而，有证据表明存在新的常见可改变风险因素以及遗传和 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，我们将通过跟踪 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) 和来自 UAB 风湿关节炎的 200 名黑人痛风患者 数据库和注册表历时一年。我们将首先研究新颖的常见可修改因素（即 含糖饮料、咖啡和茶）以降低痛风发作的风险（目标 1）。此外，我们还将翻译 最近的基因组研究数据显示，痛风护理中的精准医疗涉及生活方式和生活方式。 药物干预。具体来说，我们将检查据称涉及的尿酸盐基因的影响 糖转运（SLC2A9）和代谢基因（GCKR、IGF1R 和 INHBB）对关键危险因素的影响 用于痛风发作（目标 2）。我们还将研究 ABCG2 变体 (Q141K) 和 PRKAG2 的所谓影响 别嘌呤醇上的变体（编码 AMPK（痛风炎症的主要调节因子）的 γ 链） 对痛风发作的临床疗效，以及 SLC2A9 变体对利尿剂诱发的痛风的据称作用 照明弹（目标 3）。最后，我们将研究其他关键属性（即种族（黑人）和 CKD 状态）的作用 （第3阶段或更高））对痛风患者中痛风发作的关键触发因素的影响进行进一步的精准痛风护理 （目标 4）。这些目标解决了新的、常见的风险因素、基因-环境相互作用、 药物基因组学、种族/CKD 影响，所有这些都可以很容易地转化为临床实践 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团队广泛的 痛风研究经验，为痛风精准医疗提供关键研究成果转化。本项目 通过填补可修改的关键证据空白，将对数百万痛风患者产生重要的积极影响 有痛风发作风险的因素和相关亚组。