Functional and Integrative Omics of Recurrent Gout Flares

项目总结 痛风在美国很普遍(占成年人口的3.9%)，不仅直接影响人们的生活，而且还 与心脏代谢性疾病并存。痛风由不可预测的急性炎症或红肿发作组成。 由尿酸单钠(MSU)晶体激活单核细胞NLRP3炎性小体所致 高尿酸血症，随后IL-1的产生，以及大量炎性细胞在 受影响的关节。 免疫细胞(中性粒细胞， 巨噬细胞和单核细胞)是这种免疫反应的关键机制。在父级授予中 这个补充我们问两个问题：1)中性粒细胞和/或单核细胞在MSU体外激活时 痛风复发患者的基因表达和DNA甲基化的差异 痛风患者的闪光与没有闪光的比较？2)来自临床试验环境的痛风患者，其中治疗与靶向治疗 接受降尿酸治疗(ULT)后，是否存在基因表达和DNA甲基化的差异 有或无复发红斑的个体之间的外周血液？在这里，在这份多样性补充中，我们 会将免疫细胞和全血中的这些表达和甲基化差异与基因变异联系起来 (数量性状基因座(QTL))，并赋予这些遗传变异及其靶基因调控功能 痛风-耀斑和MSU晶体反应中的因果关系。 目标1来自两个数据集的RNA测序和全基因组基因分型和甲基化数据(痛风登记处 和Stop Gout)将用于识别痛风特异的血液和免疫细胞基因表达QTL(EQTL)和 甲基化QTL(MeQTL)。在目标2中，我们将使用实验系统，包括斑马鱼的基因模型 调节，以了解痛风相关基因调节区在哪里表达，如果遗传变异改变 调节功能以及靶基因如何影响MSU诱导的免疫反应。 我们的研究将加深我们对痛风耀斑机制及其遗传基础的了解，并最终 指出可能允许痛风的新治疗方法的研究领域。

PROJECT SUMMARY Gout is prevalent in the US (3.9% of the adult population) and not only directly impacts peoples’ lives but is also co-morbid with cardiometabolic disease. Gout consists of unpredictable episodes of acute inflammation or flares resulting from monocyte NLRP3 inflammasome activation by monosodium urate (MSU) crystals in people with hyperuricemia, the subsequent production of IL-1, and recruitment of large numbers of inflammatory cells into the affected joint. Altered gene expression and DNA methylation in response to MSU crystals in immune cells (neutrophils, macrophages and monocytes) are key mechanisms underpinning this immune response. In the parent grant to this supplement we ask two questions: 1) Do neutrophils and/or monocytes, upon ex vivo activation by MSU crystals, exhibit gene expression and DNA methylation differences between gout patients with recurrent gout flares compared to those that do not? 2) Among gout patients from a clinical trial setting, where treat-to-target urate lowering therapy (ULT) is administered, are there gene expression and DNA methylation differences from the peripheral blood between individuals with or without recurrent flares? Here, in this diversity supplement, we will link these expression and methylation differences in immune cells and whole blood to genetic variants (quantitative trait loci (QTL)) and assign regulatory function to these genetic variants and their target genes causal in the gout-flare and MSU crystal response. In Aim 1 RNA-sequencing and whole genome genotyping and methylation data from two datasets (Gout Registry and Stop Gout) will be used to identify gout-specific blood and immune-cell gene expression QTL (eQTL) and methylation QTL (meQTL). In Aim 2 we will use experimental systems, including a zebrafish model of gene regulation, to understand where gout-relevant gene regulatory regions are expressed, if the genetic variants alter regulatory function and how the target genes might influence the MSU-induced immune response. Our studies will deepen our knowledge of the mechanisms of gout flares and its genetic basis, and ultimately point to areas of research that may allow for novel treatments in gout.