Identifying Novel Biological Pathways for Gout using DNA Methylation and Genetics

翻译后摘要：确定新的生物学途径痛风使用DNA甲基化和遗传学 痛风是炎症性关节炎最常见的形式，影响约800万美国成年人。痛风患者 经历与生活质量受损和高水平医疗保健相关的剧烈疼痛发作 利用率随着痛风危险因素的日益普遍，如老年、肥胖、高血压、慢性 肾脏疾病和高尿酸血症，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，与其他风湿性疾病相比，痛风研究不足。 痛风新危险因素的发现可以增强我们对疾病易感性的理解， 确定预防和治疗目标。痛风发作是炎症反应的沉积 关节组织中的结晶导致疼痛和关节肿胀迅速加剧。 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 急性痛风易感性的变化是有限的。已知免疫反应与痛风发作有关， 包括炎性小体的激活。新的证据支持炎症与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 疾病仍有待阐明。全血中DNA甲基化的检查有可能 揭示痛风表观遗传风险因素DNA甲基化水平也可能是环境因素的中介。 以及痛风的遗传风险因素，从而可以深入了解介导痛风发作的生物学途径 或者可以作为暴露于环境危险因素的生物标志物。本研究的总体目标是 揭示表观遗传因素，可以阐明痛风易感性的生物学途径 和/或用作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 与痛风发病相关;（2）确定与血清尿酸水平相关的DNA甲基化位点， 通过（i）使用以下方法评估相关DNA甲基化位点与血清尿酸盐之间的潜在因果关系： 孟德尔随机化方法，和（ii）深入调查尿酸盐相关位点， 与血压有关;（3）开发和验证痛风风险预测模型， 来自：（i）临床，（ii）遗传和（iii）表观遗传风险因素，并检查血清尿酸盐水平以外的因素 增加了对不同性别和中长期风险的预测。这项拟议的研究将 通过识别潜在可逆的表观遗传因素加速痛风预防和治疗的研究 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， 治疗血清尿酸目标的高危患者尤为重要。

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.