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

项目摘要 痛风是一种常见的、疼痛难忍的炎性关节炎，与高尿酸血症有关。的 在过去的几十年中，痛风的患病率增加到3.9%的美国成年人（830万人）， 高水平的合并症（CoRT主题，包括慢性肾脏疾病）使其进一步复杂化 （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， 可用的药物，痛风管理仍然不理想，经常发生复发性发作， 显然需要扩大痛风护理的循证和个性化精确方法。我们 以前的波士顿在线痛风研究成功地提供了有关传统痛风作用的相关证据。 先前存在的痛风患者中痛风发作的所谓风险因素，这一点得到了最新ACR痛风研究的认可。 指南然而，有证据表明，所谓的新的常见可改变的风险因素以及遗传和 缺乏精确痛风护理所必需的其他关键属性。为了填补这个关键证据 gap，我们将通过跟踪800名痛风患者来扩展我们成功的波士顿在线痛风研究平台 来自Partners Biobank队列（N > 75，000）和来自UAB Rheumatology Arthritis的200名黑痛风患者 数据库和注册表在一年内。我们将首先研究新的常见可修改因素（即， 含糖饮料、咖啡和茶），以降低痛风发作的风险（目标1）。此外，我们将翻译 最近的基因组研究数据对痛风护理的生活方式和 药物干预。具体来说，我们将研究尿酸盐基因参与的所谓影响， 糖转运（SLC 2A 9）和代谢基因（GCKR，IGF 1 R和INHBB）对关键风险因素的影响 痛风发作（目标2）。我们还将研究ABCG 2变体（Q141 K）和PRKAG 2 变体（编码AMPK的γ链（痛风炎症的主要调节因子）） 痛风发作的临床疗效，以及SLC 2A 9变体对利尿剂诱导的痛风的作用 照明弹（目标3）。最后，我们将研究其他关键属性的作用（即，人种（黑人）和CKD状态 （3期或更高））对痛风患者中痛风发作的关键触发因素的影响，以进一步精确痛风护理 (Aim 4）。这些目标针对新的、常见的风险因素、基因-环境相互作用， 药物基因组学和种族/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，创新和具有成本效益的研究设计利用了我们集团广泛的 痛风研究经验，为痛风精准医学提供关键研究翻译。这个项目 将对数百万痛风患者产生重要的积极影响， 痛风发作的危险因素和相关亚组。

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.