Multi-Omics for Chronic Kidney Disease

慢性肾脏病的多组学

• 批准号: 10744557
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 83.67万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744557
• 关键词: APOL1 gene; Acceleration; Address; Affect; African American; African American population; African ancestry; Anemia; Blood; Bone Diseases; Cardiovascular Diseases; Caring; Chronic; Chronic Kidney Failure; Classification; Clinical; Complex; Data; Diabetes Mellitus; Diagnosis; Disease; Disparity; Economic Factors; Economics; Education; Electrolytes; Ensure; Environment; Environmental Exposure; Environmental Monitoring; Epidemiology; Epigenetic Process; Equity; Ethics; Etiology; Exclusion; Exposure to; Filtration; Frequencies; Genetic; Genetic study; Genomics; Glomerular Filtration Rate; Goals; Health; Heritability; Hispanic; Hispanic Populations; Histologic; Human Genetics; Immune; Immune System Diseases; Individual; Injury; Injury to Kidney; Intervention Studies; Kidney Diseases; Lead; Leadership; Life; Lupus; Malignant Neoplasms; Metabolic dysfunction; Metabolism; Methods; Minority; Minority Groups; Mission; Molecular; Molecular Disease; Morbidity - disease rate; Nephrology; Outcome; Participant; Patients; Pattern; Phenotype; Play; Population Heterogeneity; Positioning Attribute; Prevalence; Prospective Studies; Prospective cohort; Proteomics; Protocols documentation; Public Health; Renal function; Reproducibility of Results; Research; Research Design; Risk; Role; Science; Site; Socioeconomic Factors; Standardization; Systemic disease; Toxic Environmental Substances; Toxicant exposure; Underrepresented Minority; Underrepresented Populations; United States National Institutes of Health; Urine; Work; burden of illness; clinical care; cohort; comorbidity; cost; design; disorder control; disorder risk; disorder subtype; epidemiology study; experience; genetic predictors; genetic risk factor; genetic testing; health equity promotion; high risk; high throughput technology; hispanic community; improved; innovation; kidney biopsy; kidney dysfunction; metabolomics; molecular marker; molecular subtypes; mortality; multidisciplinary; multiple omics; nephrotoxicity; non-diabetic; novel; outreach; pollutant; precision medicine; prospective; recruit; risk variant; social; social factors; social health determinants; statistics; stressor; support network; transcriptomics

PROJECT SUMMARY Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality, with a prevalence estimated at 13% in the U.S. that continues to increase annually. The etiology of CKD is complex, with both genetic – including monogenetic and polygenic – and environmental contributions playing major roles. African American and Hispanic communities in the U.S. are disproportionally affected by CKD; environmental, socioeconomic, and inherited factors, such as APOL1 risk genotypes, are likely contributing to these disparities. Multi-omic approaches including genetics, epigenetics, transcriptomics, proteomics, and metabolomics are high- throughput technologies being leveraged for precision medicine that hold great potential to improve diagnosis and clinical care for complex diseases such as CKD. As part of the Multi-omics Health and Disease Consortium, this proposal will establish a Disease Study Site (DSS) focused on CKD. Our rationale for selecting CKD is three- fold: 1) CKD has high cost and public health impact in the U.S. and disproportionally affects minority populations underrepresented in genomic research; 2) CKD represents an important modifier of multi-omic profiles in other common conditions; and 3) there is an urgent, unmet need to provide molecular disease subclassification in CKD – and in particular non-diabetic CKD – as the current diagnosis relies solely on functional rather than molecular criteria. Our hypothesis is that longitudinal blood and urine multi-omics can provide non-invasive means to better subclassify non-diabetic CKD, and thus provide a new precision medicine-based approach for this condition. In alignment with the mission of the consortium, our DSS also aims to address current disparities in kidney disease and genomics, considering that individuals of non-European ancestry are overwhelming under-represented in human genetic and multi-omic studies of kidney disease. To this end, we propose a prospective study of 200 CKD patients and 100 non-CKD controls of diverse ancestral backgrounds, with at least 75% of participants from groups underrepresented in research. We will address the following questions: What are the molecular correlates of longitudinal decline in renal function in ancestrally diverse patients? Are there specific molecular subtypes of non-diabetic CKD identifiable by longitudinal multi-omics? What are the roles of environmental exposures, social and economic stressors, and genetics in determining molecular CKD subtypes? Our team involves national leaders in Precision Medicine and has a track record of successful execution of genetic, epidemiologic, and interventional studies involving diverse underrepresented populations. We will coordinate efficient local recruitment of our prospective cohort using innovative outreach methods that address barriers to recruiting under-represented groups. Our long-term goal is to promote health equity and challenge the existing clinical paradigms in CKD and multi-omics more broadly to advance precision medicine.

项目摘要 慢性肾脏病（CKD）是一种常见的复杂疾病，与高发病率和死亡率相关， 在美国的患病率估计为13%，并且每年继续增加。CKD的病因复杂， 遗传因素-包括单基因和多基因因素-和环境因素都起主要作用。 美国的非洲裔美国人和西班牙裔社区受到CKD的严重影响;环境， 社会经济和遗传因素，如APOL 1风险基因型，可能导致这些差异。 包括遗传学、表观遗传学、转录组学、蛋白质组学和代谢组学在内的多组学方法是高效率的。 用于精准医学的通量技术具有改善诊断的巨大潜力 以及慢性肾病等复杂疾病的临床护理。作为多组学健康和疾病联盟的一部分， 该提案将建立一个专注于慢性肾脏病的疾病研究中心（DSS）。我们选择CKD的理由有三个- 1）CKD在美国具有高成本和公共卫生影响，并对少数群体产生不利影响 在基因组研究中代表性不足; 2）CKD代表了其他研究中多组学特征的重要修饰剂 常见疾病;以及3）迫切需要提供CKD的分子疾病亚分类 - 特别是非糖尿病性CKD，因为目前的诊断仅依赖于功能而不是分子 的搜索.我们的假设是，纵向血液和尿液多组学可以提供非侵入性手段，以更好地 对非糖尿病CKD进行细分，从而为这种疾病提供了一种新精确的基于医学的方法。在 与联盟的使命一致，我们的DSS还旨在解决目前肾脏疾病的差异 和基因组学，考虑到非欧洲血统的个人在欧洲的代表性不足， 肾脏疾病的人类遗传学和多组学研究。为此，我们提出了一项前瞻性研究， CKD患者和100名不同祖先背景的非CKD对照，至少75%的参与者来自 在研究中代表性不足的群体。我们将讨论以下问题： 血统不同的患者肾功能纵向下降？是否有特定的分子亚型 通过纵向多组学可识别的非糖尿病CKD？环境暴露、社会 和经济压力，以及遗传学在确定分子CKD亚型？我们的团队涉及国家 精准医学的领导者，并拥有成功执行遗传学，流行病学和 涉及不同代表性不足人群的干预性研究。我们将协调高效的本地 使用创新的外展方法招募我们的前瞻性队列，解决招募障碍 代表性不足的群体。我们的长期目标是促进健康公平，挑战现有的临床 更广泛地应用于CKD和多组学的范例，以推进精准医学。