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: 10444188
• 负责人: HYON K CHOI
• 金额: $ 77.93万
• 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/10444188
• 关键词: Adult; Affect; African American population; Ascorbic Acid; Asia; Asian; Atherosclerosis Risk in Communities; Bacteria; Biological Markers; Biology; Branched-Chain Amino Acids; Butyrates; Caring; Case Study; Cholesterol; Citric Acid; Clinical; Coffee; Country; Crystallization; Data; Development; Disease; Emergency department visit; Estrone; Estrone-Sulfate; Etiology; Flare; Follow-Up Studies; Foundations; Fructose; Funding; Gas-Liquid 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; 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; Time; 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; novel; phenome; population based; predictive tools; prospective; sex; sociodemographics; stool sample; success; trait

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).

痛风是一种导致最常见炎症性关节炎的代谢疾病，会导致极度疼痛 由于代谢物的原因，痛风风险受到生活方式的影响，并且越来越多。 由于流行的“西方”生活方式，痛风的疾病负担在全球范围内不断上升，目前影响着 4% 的美国成年人 (>9 百万）随着急诊就诊和住院治疗的增加，通过美国国立卫生研究院资助的研究，我们取得了进展。 在识别痛风的生活方式和遗传风险因素、量化所谓的因素以及 发现新的危险因素和新的保护因素，以及痛风的常见遗传变异。 尽管如此，在临床痛风的进展过程中仍然存在一些基本问题；长期高尿酸血症（HU）是 必要的，但还不够（只有约 20% 的人会患上痛风）此外，独特性别背后的生物学因素也很重要。 痛风的差异（男性患病率比女性高 3 倍）目前仍不清楚。 代谢组代表了基因组和表型组之间一个引人注目的目标特征，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 事实上，某些代谢物对于诱导训练有素的免疫力和调节炎症至关重要。 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 促炎症状态，HU 进展的所有相关途径。 代谢组学研究（6 项来自亚洲）加上我们来自英国生物银行的新数据表明支链 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，进而调节循环性激素水平。 此外，痛风患者体内的细菌也减少了，这些细菌也可以通过尿酸分解来降低尿酸盐水平。 作为丁酸盐，一种短链游离脂肪酸代谢物，能够减少痛风炎症。 尽管前景广阔，但目前尚不清楚这些组学特征是否会导致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）或混杂因素，其在亚洲或男性之外的普遍性尚不清楚。 建立在我们之前 R01 的成功和长期代谢组学研究的丰硕记录的基础上 卫生专业人员后续研究和两项护士健康研究，这项相互竞争的更新提案 进行第一个基于人群的前瞻性痛风代谢组学研究并进行外部验证 在多元化队列（ARIC，其中 62% 为非裔美国人）中进行因果推断分析（目标 1），并阐明 肠道微生物群的作用（目标 2），数十年确诊的痛风病例和丰富的生活方式暴露/生物标志物 我们的目标是确定痛风风险的关键组学，类似于已确定的强因果代谢物。 （例如，胆固醇对冠状动脉事件的影响）。已确定的因素有望带来新的预防和治疗方法。 尿酸以外的痛风选择和新颖的预测工具，包括从 HU 到临床痛风的进展 （一级预防）或可能的复发风险，以指导整体痛风护理（二级预防）。