Non-APOL1 genetic factors and kidney transplant outcomes

非 APOL1 遗传因素与肾移植结果

• 批准号: 10717171
• 负责人: KRZYSZTOF KIRYLUK
• 金额: $ 72.38万
• 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: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717171
• 关键词: APOL1 gene; Achievement; Address; Affect; African; African American; African ancestry; Allografting; Ancillary Study; Case Study; Clinical; Collaborations; Copy Number Polymorphism; Data; Data Set; Diagnostic; Disparity; Donor person; End stage renal failure; Enrollment; Ensure; Epidemiologic Methods; Epidemiology; Exposure to; Failure; Generations; Genes; Genetic; Genetic Diseases; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Graft Survival; Human Genetics; Human Genome; Individual; International; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Lead; Medicine; Methods; Minor Histocompatibility Antigens; Motivation; Nature; Outcome; Outcome Study; Parents; Participant; Patients; Population; Positioning Attribute; Proteins; Reproducibility of Results; Research; Research Personnel; Retrospective Studies; Risk; Role; Safety; Scanning; Testing; Time; Tissue-Specific Gene Expression; Transplantation; Untranslated RNA; Validation; Variant; Work; allograft rejection; ancestry analysis; clinical care; clinical practice; cohort; exome; exome sequencing; experience; gene product; genetic profiling; genetic risk factor; genetic testing; genome wide association study; genome-wide; high risk; improved; innovation; kidney allograft; loss of function; novel; precision medicine; prospective; risk variant; statistics

Abstract This is an ancillary study to the prospective APOLLO (APOL1 Long-term Kidney Transplantation Outcomes) cohort of 2,800 kidney transplant donor-recipient pairs. The parent study aims to test the impact of APOL1 risk genotypes on kidney transplantation outcomes. Here, we propose to test the role of additional genetic factors other than APOL1 in determining allograft outcomes. Accordingly, we propose to expand the scope of the APOLLO study to generate high-quality genome-wide SNP and exome sequence data for all 2,800 donor- recipient pairs enrolled by the network. Our proposal addresses the existing disparities in research and clinical care, since African-ancestry patients with end stage kidney disease are currently under-represented in genetic studies and have worse transplantation outcomes compared to non-African ancestry patients. Our overarching hypothesis is that there are multiple additional genetic factors in this population that convey the risk of allograft loss independently of APOL1. Our recent work clearly demonstrates that polygenic background and APOL1 risk genotypes have additive effects on the risk of kidney disease in individuals of African ancestry. Our newly proposed genome-wide polygenic score (GPS) combining polygenic and APOL1 risk provided substantially improved prediction of kidney disease. There is now an urgent need to test whether combining donor polygenic and APOL1 risk improves the prediction of allograft outcomes. Additionally, our proposed generation of genome-wide genetic data will facilitate unbiased scans for specific APOL1 modifiers with an effect on graft survival. Lastly, the APOLLO study provides us with a unique opportunity to perform genetic compatibility scans in full donor-recipient pairs. We aim to test our original “genomic collision” hypothesis at the LIMS1 locus under which the recipients carrying gene-disrupting variants are at a higher risk of rejection when exposed to a graft expressing intact gene products. We will then expand this hypothesis to various types of genetic variation genome-wide, including gene-disrupting copy number variants, predicted loss-of-function variants, and even missense variants. Any positive findings from our discovery studies will be tested for validation in the ancestrally diverse international cohorts of the iGeneTRAiN consortium. Our experienced team of investigators from the fields of human genetics, precision medicine, kidney transplant epidemiology, and statistics has a track record of successful collaboration and execution of genetic studies involving thousands of participants. We believe this proposal will challenge the existing clinical paradigms in kidney transplantation, and our expert team is ideally positioned to lead this effort.

抽象的 这是对前瞻性阿波罗的辅助研究（APOL1长期肾脏移植结果） 队列2,800个肾脏移植供体 - 接收对。家长研究旨在测试APOL1风险的影响 肾移植结果的基因型。在这里，我们建议测试其他遗传因素的作用 除了确定同种囊结果的APOL1以外。根据，我们建议扩大 Apollo研究为所有2,800个捐助者生成高质量的全基因组SNP和外显子组序列数据 收件人对网络注册。我们的建议解决了研究和临床的现有差异 护理，由于目前遗传性的非洲官员患者目前的代表性不足 与非非洲血统患者相比，研究和移植结果较差。我们的总体 假设是，该人群中还有多种其他遗传因素传达出异源的风险 损失独立于apol1。我们最近的工作清楚地表明了多基因背景和apol1 风险基因型对非洲血统个体肾脏疾病的风险有其他影响。我们的新 拟议的全基因组多基因评分（GPS）结合了多基因和APOL1风险 改善了肾脏疾病的预测。现在迫切需要测试是否将供体多基因结合在一起 APOL1风险改善了同种异体结局的预测。此外，我们提出的一代 全基因组遗传数据将促进对特定APOL1修饰符的无偏扫描，并影响移植 生存。最后，阿波罗研究为我们提供了执行遗传兼容性的独特机会 扫描完整的供体 - 院子对。我们旨在测试LIMS1基因座的原始“基因组碰撞”假设 在暴露于A时，携带基因干扰变体的接收者的拒绝风险更高 表达完整基因产物的移植物。然后，我们将将这一假设扩展到各种类型的遗传变异 全基因组，包括基因干扰拷贝数变体，预测功能丧失变体，甚至 错义变体。我们的发现研究中的任何积极发现都将在 伊格因特因会财团的祖先多样化的国际人群。我们经验丰富的调查员团队 从人类遗传学，精密医学，肾脏移植流行病学和统计的领域具有 成功合作和执行涉及数千名参与者的遗传研究的记录。 我们认为，该建议将挑战肾脏移植中现有的临床范例，我们的专家 理想的是领导这一努力。