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).

痛风是一种代谢性疾病，导致最常见的炎症性关节炎，导致令人痛苦的痛苦 耀斑和关节损坏。使用尿酸尿酸盐为因果代谢产物，痛风风险受到生活方式的影响，并且越来越多 痛风的疾病燃烧在全球范围内燃烧，现在影响了4％的美国成年人（> 9 百万），急诊室就诊和住院次数上升。通过NIH资助的研究，我们进行了 确定痛风的生活方式和遗传风险因素，量化所谓的因素以及 发现新颖的危险因素和新的受保护因素，以及事件痛风的常见遗传变异。 尽管如此，基本问题仍然是临床痛风的进展。长时间的高尿炎（HU）为 必要，但不足（只有约20％的GOOUT）。此外，独特的性爱背后的生物学 GOOUT的差异（男性的患病率是女性的3倍）仍然不清楚。为此， 代谢组代表了基因组和现象之间的引人入胜的目标特征，以阐明疾病 机制，倾向，进展和预测，尤其是用于代谢炎症条件（例如 痛风。实际上，某些代谢产物对于诱导训练的免疫力和调节炎症至关重要 基因表达，而其他基因表达可能会抑制盖蒂注射，增加尿酸降水或影响 促炎状态，所有相关的途径。在多个与之相关的 代谢组学研究，来自亚洲的6个，加上我们来自英国生物库的新数据，已经实施了分支链 氨基酸横截面。此外，性激素代谢产物虽然与痛风风险有关 影响肠道菌群的组成，从而调节循环性激素水平。 此外，让患者表现出细菌的耗竭，还可以通过尿液解释降低尿酸盐的水平 作为丁酸酯，短链无链的脂肪酸代谢产物能够减少痛风注射。尽管 高度希望，这些OMICS配置文件是否有助于痛风风险或代表的“标记”仍然未知 既定的跳动（反向原因）或混淆，其亚洲或男性以外的普遍性尚不清楚。 以我们先前的R01成功和长期代谢组学研究的富有成果的记录为基础 卫生专业人员的后续研究和两项护士的健康研究，这项竞争的续约建议 对事件脱身进行首次前瞻性，基于人群的代谢组学研究，并进行外部验证 在潜水员队列中（ARIC，有62％的非洲裔美国人）和因果推理分析（AIM 1），并澄清 肠道菌群的角色（AIM 2），具有数十年的痛风病例和丰富的生活方式暴露/生物标志物 数据。我们的目的是确定痛风风险中的关键OMIC，类似于建立的，强烈的因果代谢物 （例如，用于冠状动脉事件的胆固醇）。确定的因素具有新的预防和治疗的承诺 选项以及新的痛风的新型预测工具，包括从HU到临床痛风的发展 （初级预防）或可能会发生反复发作的风险来指导整体痛风护理（二级预防）。