Multi-Omics for Chronic Kidney Disease

慢性肾脏病的多组学

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要慢性肾脏疾病（CKD）是与高发病率和死亡率相关的常见复杂疾病，美国估计的患病率估计为13％，每年继续增加。 CKD的病因很复杂，具有遗传学（包括单基因和多基因）以及扮演着主要作用的环境贡献。美国的非洲裔美国人和西班牙裔社区受到CKD的不成比例影响；环境，社会经济和遗传因素（例如APOL1风险基因型）可能会导致这些差异。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词方法是高的吞噬技术被利用用于精确医学，具有改善诊断的巨大潜力以及复杂疾病（例如CKD）的临床护理。作为多摩智健康和疾病财团的一部分，该提案将建立一个以CKD为目的的疾病研究地点（DSS）。我们选择CKD的理由是三个折：1）CKD在美国具有很高的成本和公共卫生影响，并且对少数民族的影响不成比例基因组研究的代表性不足； 2）CKD代表其他多摩尼克的重要修饰符常见条件； 3）在CKD中提供分子疾病亚分类存在紧急，未满足的需求 - 特别是非糖尿病CKD - 由于当前的诊断仅依赖于功能而非分子标准。我们的假设是，纵向血液和尿液多词可以提供非侵入性手段以改善子分类非糖尿病CKD，因此为这种情况提供了一种新的基于精确医学的方法。在与财团的使命保持一致，我们的DSS还旨在解决当前的肾脏疾病分布和基因组学，考虑到非欧洲血统的个人的代表性不足人类的肾脏疾病遗传学和多词学研究。为此，我们提出了200个前瞻性研究 CKD患者和100名非CKD对照组的祖先背景，至少有75％的参与者来自小组的研究不足。我们将解决以下问题：分子相关是什么祖先多样化患者的肾功能纵向下降？是否有特定的分子亚型通过纵向多词可以识别的非糖尿病CKD？环境暴露，社会的角色是什么和经济压力源以及确定分子CKD亚型的遗传学？我们的团队涉及国家精密医学领导者，并有成功执行遗传，流行病学和涉及潜水员代表性不足的人群的介入研究。我们将有效地协调本地使用创新的外展方法招募我们的潜在队列，以解决招聘障碍代表性不足的群体。我们的长期目标是促进健康公平并挑战现有的临床在CKD和多媒体中的范例更广泛地推进精度医学。