Identifying Novel Biological Pathways for Gout using DNA Methylation and Genetics

摘要：利用DNA甲基化和遗传学寻找痛风的新生物途径 痛风是最常见的炎症性关节炎，影响着大约800万美国成年人。痛风患者 体验与生活质量受损和高水平医疗保健相关的剧烈疼痛 利用率。随着痛风危险因素的增加，如老年、肥胖、高血压、慢性 肾脏疾病、高尿酸血症、痛风的发病率和患病率及其公共卫生 重要性都在上升。然而，与其他风湿病相比，痛风的研究还不够深入。 发现痛风的新危险因素可以提高我们对痛风疾病易感性和 确定预防和治疗的目标。痛风发作是对沉积的炎性反应 关节组织中的尿酸一钠结晶导致关节疼痛和肿胀迅速加剧(S)。 然而，大多数高尿酸血症患者不会发生痛风。我们对个人的理解 急性痛风的易感性变异是有限的。已知的免疫反应与痛风发作有关， 包括激活炎症小体。新出现的证据支持炎症和DNA之间的联系 甲基化水平。然而，影响DNA甲基化水平的因素及其对慢性疾病的影响 疾病仍有待阐明。全血DNA甲基化检测有可能 发现痛风的表观遗传危险因素。DNA甲基化水平也可能是环境变化的中介 和痛风的遗传风险因素，因此可以深入了解调节痛风发作的生物途径 或可作为暴露于环境风险因素的生物标志物。这项研究的首要目标是 揭示可阐明痛风易感性的生物途径的表观遗传因素 和/或作为预测痛风的生物标志物。我们的目标是：(1)确定DNA甲基化位点 与痛风事件相关；(2)确定与血清尿酸水平相关的DNA甲基化位点 通过(I)评估相关DNA甲基化位点和血清尿酸之间的潜在因果关系 孟德尔随机化方法，以及(Ii)对具有以下特征的尿酸盐相关部位的深入调查 与血压有关；(3)开发和验证纳入数据的痛风风险预测模型 来自：(I)临床、(Ii)遗传和(Iii)表观遗传风险因素，并检查超出血清尿酸水平的因素 增加了跨性别和中长期的风险预测。这项拟议的研究将 识别潜在可逆表遗传因素加快痛风防治研究 与痛风和尿酸盐水平有关。痛风风险预测模型将为风险预测奠定基础 未来痛风治疗和管理干预试验的分层策略，特别是在高风险人群中 对高危患者的治疗，以血尿酸为目标尤为重要。

Abstract: Identifying Novel Biological Pathways for Gout using DNA Methylation and Genetics Gout is the most common form of inflammatory arthritis and affects ~8 million U.S. adults. Patients with gout experience intensely painful flares associated with impaired quality of life and high levels of healthcare utilization. With increasing prevalence of risk factors for gout, such as older age, obesity, hypertension, chronic kidney disease, and hyperuricemia, the incidence and prevalence of gout and its public health importance are all rising. However, gout is understudied compared to other rheumatologic conditions. Discovery of novel risk factors for gout can enhance our understanding of the disease susceptibility and identify targets for prevention and treatment. Gout attacks are inflammatory responses to the deposition of monosodium urate crystals in articular tissues causing rapidly intensifying painful and swollen joint(s). However, most individuals with hyperuricemia do not development gout. Our understanding of individual variation in susceptibility to acute gout is limited. The immune response is known to be involved in gout flares, including activation of the inflammasome. Emerging evidence supports links between inflammation and DNA methylation levels. However, factors influencing DNA methylation levels and their consequences for chronic disease remain to be elucidated. The examination of DNA methylation in whole blood has the potential to uncover epigenetic risk factor for gout. DNA methylation levels may also be intermediaries of environmental and genetic risk factors for gout and thus could yield insight into the biological pathways mediating gout flares or may serve as biomarkers for exposure to environmental risk factors. The overarching goal of this study is to uncover epigenetic factors that can illuminate the biological pathways underlying gout susceptibility and/or serve as biomarkers for the prediction of gout. Our aims are : (1) to identify DNA methylation sites associated with incident gout; (2) to identify DNA methylation sites associated with serum urate levels followed by (i) evaluating the potential causal relation between associated DNA methylation sites and serum urate using a Mendelian randomization approach, and (ii) an in-depth investigation of the urate-associated sites that have been linked to blood pressure; (3) to develop and validate risk prediction models for gout incorporating data from: (i) clinical, (ii) genetic and (iii) epigenetic risk factors, and examine how factors beyond serum urate levels add to risk prediction across sexes and over intermediate and longer time periods. This proposed study will accelerate research on gout prevention and treatment by identifying potentially reversible epigenetic factors related to incident gout and urate levels. The gout risk prediction models will lay the foundation for risk stratification strategy for future intervention trials for gout treatment and management, particularly among high- risk patients in whom treatment to serum urate target is particularly important.