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.

摘要 这是对预期的Apollo(APOL1长期肾移植结果)的辅助研究 2800对肾脏移植供受者对的队列。母公司的研究旨在测试APOL1风险的影响 基因分型对肾移植结果的影响。在这里，我们建议测试额外的遗传因素的作用 而不是APOL1来决定同种异体移植的结果。因此，我们建议扩大 阿波罗研究为所有2,800名捐赠者生成高质量的全基因组SNP和外显子组序列数据- 网络注册的收件人对。我们的建议解决了研究和临床方面的现有差距 护理，因为患有终末期肾病的非洲血统患者目前在遗传方面的代表性不足 而且与非非洲血统的患者相比，移植结果更差。我们最重要的是 假设在这个群体中有多个额外的遗传因素传递同种异体移植的风险。 与APOL1无关的损失。我们最近的工作清楚地表明，多基因背景和载脂蛋白1 在非洲血统的个体中，风险基因型对肾脏疾病的风险具有相加效应。我们的新品 建议的全基因组多基因评分(GPS)结合了多基因和APOL1风险，提供了大量的 改善了对肾脏疾病的预测。现在迫切需要测试联合供体多基因 APOL1风险改善了对同种异体移植结果的预测。此外，我们建议的一代 全基因组的遗传数据将有助于无偏扫描特定的APOL1修饰物对移植物的影响 生死存亡。最后，阿波罗研究为我们提供了一个执行遗传兼容性的独特机会 以完整的供受者对进行扫描。我们的目标是在LIMS1基因座测试我们最初的“基因组碰撞”假说 在这种情况下，携带基因干扰变体的受者在暴露于 表达完整基因产物的嫁接。然后我们将把这一假设扩展到各种类型的遗传变异。 全基因组范围，包括基因干扰拷贝数变异，预测功能丧失变异，甚至 错误的变种。我们探索研究中的任何积极发现都将在 IGeneTRAiN财团的祖先不同的国际队列。我们经验丰富的调查团队 从人类遗传学、精准医学、肾移植流行病学和统计学领域都有 成功合作和执行涉及数千名参与者的基因研究的跟踪记录。 我们相信这项建议将挑战现有的肾移植临床范例，我们的专家 团队是领导这项工作的理想人选。