NOVEL METABOLITE AND MICROBIOTA PATHWAYS FOR HYPERURICEMIA AND GOUT

高尿酸血症和痛风的新代谢物和微生物途径

• 批准号: 10612960
• 负责人: HYON K CHOI
• 金额: $ 78.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612960
• 关键词: Adult; Affect; African American population; Ascorbic Acid; Asia; Asian; Atherosclerosis Risk in Communities; Bacteria; Beverages; Biological Markers; Biology; Black race; Branched-Chain Amino Acids; Butyrates; Caring; Case Study; Cholesterol; Citric Acid; Clinical; Coffee; Country; Dairying; Data; Development; Diet; Disease; Emergency department visit; Estrone; Estrone-Sulfate; Etiology; Flare; Follow-Up Studies; Foundations; Fructose; Funding; Gas Chromatography; Gene Expression; Generations; Genome; Gonadal Steroid Hormones; Gout; Health Professional; Heart; High Prevalence; Hormones; Hospitalization; Hyperuricemia; Immunity; Individual; Inflammation; Inflammatory; Inflammatory Arthritis; Intestines; Ketone Bodies; Life Style; Liquid Chromatography; Mass Spectrum Analysis; Medical; Mendelian randomization; Metabolic; Metagenomics; Microbe; Nested Case-Control Study; Network-based; Nonesterified Fatty Acids; Nurses' Health Study; Pain; Pathogenesis; Pathway interactions; Patients; Plasma; Precipitation; Predisposition; Prevalence; Prevention; Prevention strategy; Primary Prevention; Prospective, cohort study; Pyrrolidonecarboxylic Acid; Recurrence; Regulation; Research; Resources; Risk; Risk Factors; Role; Sampling; Secondary Prevention; Sex Differences; Statistical Methods; Steroids; Taxonomy; Testing; Testosterone; Training; United States National Institutes of Health; Urate; Validation; Woman; androgenic; biobank; burden of illness; cardiometabolism; cohort; coronary event; dehydroepiandrosterone; dietary; equol; follow-up; genetic risk factor; genetic variant; genome wide association study; gut microbiome; gut microbiota; hormone regulation; insight; joint injury; lifestyle data; male; men; metabolome; metabolomics; microbial; microbiome; microbiota; monocyte; novel; phenome; population based; predictive tools; prospective; sex; sociodemographics; stool sample; success; trait; western diet

Gout, a metabolic condition causing the most common inflammatory arthritis, leads to excruciatingly painful flares and joint damage. With urate a causal metabolite, gout risk is affected by lifestyle, and with increasingly prevalent “western” lifestyles, the disease burden of gout has risen globally, now affecting 4% of US adults (>9 million) with rising emergency room visits and hospitalizations. Through NIH-funded research, we have made significant advances in identifying lifestyle and genetic risk factors for gout, quantifying purported factors, and discovering novel risk factors and new protective ones, as well as common genetic variants for incident gout. Still, fundamental questions remain in the progression to clinical gout; prolonged hyperuricemia (HU) is necessary, but not sufficient (only ~20% develop gout). Furthermore, the biology behind the distinctive sex difference in gout (>3 times higher prevalence in men than women) remains largely unclear. To that end, the metabolome represents a compelling target trait between genome and phenome to elucidate disease mechanisms, predisposition, progression and prediction, especially for metabolic-inflammatory conditions like gout. Indeed, certain metabolites are crucial for induction of trained immunity and regulation of inflammatory gene expression, while others may suppress gouty inflammation, increase urate precipitation, or affect proinflammatory status, all relevant pathways for progression from HU. Amongst the multiple gout-related metabolomics studies, 6 from Asia, plus our new data from UK Biobank, have implicated branched-chain amino acids cross-sectionally. Furthermore, sex hormone metabolites, while implicated in gout risk, also affect the composition of gut microbiota, which can, in turn, modulate circulating sex hormone levels. Moreover, gout patients showed depletions of bacteria that can lower urate levels through uricolysis, as well as butyrate, a short chain free fatty acid metabolite capable of reducing gouty inflammation. While highly promising, it remains unknown if these omics profiles contribute to gout risk or represent ‘markers’ of established gout (reverse causation) or confounding, and their generalizability beyond Asia or males is unclear. Building on our prior R01 success and fruitful track record of long-term metabolomics research in the Health Professionals Follow-up Study and two Nurses’ Health Studies, this competing renewal proposes to conduct the first prospective, population-based metabolomics study of incident gout with external validation in a diverse cohort (ARIC, with 62% African Americans) and causal inference analysis (Aim 1), and clarify the roles of gut microbiota (Aim 2), with decades of confirmed gout cases and rich lifestyle exposure/biomarker data. We aim to determine pivotal omics in gout risk, analogous to established, strongly causal metabolites (e.g., cholesterol for coronary events). The identified factors hold the promise of new prevention and treatment options as well as novel predictive tools for gout beyond urate, including progression from HU to clinical gout (primary prevention) or possibly risk of recurrent flares to guide holistic gout care (secondary prevention).

痛风是一种代谢性疾病，可引起最常见的炎症性关节炎， 耀斑和关节损伤。由于尿酸盐是一种致病代谢物，痛风风险受生活方式的影响， 流行的“西方”生活方式，痛风的疾病负担在全球范围内上升，现在影响到4%的美国成年人（>9 随着急诊室就诊和住院人数的增加，通过NIH资助的研究， 在确定痛风的生活方式和遗传风险因素，量化所谓的因素方面取得了重大进展， 发现新的风险因素和新的保护因素，以及痛风事件的常见遗传变异。 尽管如此，在临床痛风的进展中仍然存在根本问题;长期高尿酸血症（HU）是 这是必要的，但还不够（只有约20%的人会患痛风）。此外，独特性别背后的生物学 痛风的差异（男性患病率比女性高3倍以上）在很大程度上仍不清楚。为此， 代谢组是介于基因组和表型组之间的一个引人注目的目标性状，可以阐明疾病 机制，易感性，进展和预测，特别是对于代谢-炎症性疾病，如 痛风。事实上，某些代谢物对于诱导训练的免疫力和调节炎症反应是至关重要的。 基因表达，而其他可能抑制痛风炎症，增加尿酸盐沉淀，或影响 促炎状态，HU进展的所有相关途径。在众多与痛风有关的 来自亚洲的代谢组学研究6，加上我们来自英国生物库的新数据， 氨基酸的横截面。此外，性激素代谢物，虽然与痛风风险有关， 影响肠道微生物群的组成，这反过来又可以调节循环性激素水平。 此外，痛风患者也表现出通过尿酸分解降低尿酸盐水平的细菌减少， 如丁酸盐，一种能够减少痛风炎症的短链游离脂肪酸代谢物。而 非常有希望，但仍然不清楚这些组学特征是否有助于痛风风险或代表痛风的“标志物”。 已确定的痛风（反向因果关系）或混淆，其在亚洲或男性以外的普遍性尚不清楚。 基于我们先前R 01的成功和在以下领域长期代谢组学研究的富有成效的记录， 卫生专业人员后续研究和两项护士健康研究，这次竞争性更新提议 进行第一个前瞻性的，基于人群的代谢组学研究，并进行外部验证 在一个不同的队列（ARIC，62%的非洲裔美国人）和因果推理分析（目标1），并澄清 肠道微生物群的作用（目标2），数十年来确诊的痛风病例和丰富的生活方式暴露/生物标志物 数据我们的目标是确定痛风风险的关键组学，类似于已建立的，强烈因果代谢物 (e.g.,胆固醇用于冠状动脉事件）。已确定的因素为新的预防和治疗带来了希望 选择以及新的预测工具，痛风超越尿酸盐，包括从HU进展到临床痛风 （一级预防）或可能复发的风险，以指导整体痛风护理（二级预防）。