Multi-Omics for Chronic Kidney Disease

项目总结 慢性肾脏疾病(CKD)是一种常见的复杂疾病，与高发病率和死亡率有关， 据估计，美国的患病率为13%，而且每年都在继续上升。慢性肾脏病的病因很复杂， 遗传--包括单基因和多基因--和环境贡献都发挥着主要作用。 美国的非裔美国人和西班牙裔社区不成比例地受到CKD的影响；环境， 社会经济因素和遗传因素，如APOL1风险基因类型，可能是造成这些差异的原因。 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度... 吞吐量技术被用于精准医学，具有提高诊断的巨大潜力 以及CKD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， 这项提议将建立一个专注于慢性肾脏病的疾病研究网站(DSS)。我们选择CKD的理由有三个： 折叠：1)CKD在美国具有高成本和公共健康影响，并不成比例地影响少数族裔人口 在基因组研究中的代表性不足；2)CKD代表了在其他植物中多基因组图谱的重要修饰 常见情况；以及3)在慢性肾脏病中提供分子疾病亚分类的迫切需求尚未得到满足 -尤其是非糖尿病慢性肾脏病--因为目前的诊断完全依赖于功能而不是分子 标准。我们的假设是，纵向血和尿的多重组学可以提供更好的非侵入性手段 对非糖尿病CKD进行细分，从而为这种疾病提供了一种新的基于精确医学的方法。在……里面 与该联盟的使命相一致，我们的DSS还旨在解决目前肾脏疾病方面的差异 和基因组学，考虑到非欧洲血统的个人在 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200人的前瞻性研究 CKD患者和100名祖先背景不同的非CKD对照组，至少75%的参与者来自 在研究中代表性不足的群体。我们将解决以下问题：分子关联是什么 在祖先不同的患者中肾功能纵向下降的风险？有没有特定的分子亚型 纵向多组学可识别的非糖尿病慢性肾脏病？环境暴露、社会暴露的作用是什么？ 以及决定分子CKD亚型的经济压力因素和遗传因素？我们的球队有国家队参加 精准医学领域的领导者，并在成功执行遗传、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 使用解决招聘障碍的创新外展方法招募我们的潜在队列 代表不足的群体。我们的长期目标是促进健康公平，挑战现有的临床 在CKD和更广泛的多组学中的范例，以促进精确医学。

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.