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 这是前瞻性 APOLLO（APOL1 长期肾移植结果）的辅助研究 母体研究的目的是测试 APOL1 风险的影响，该队列由 2,800 对肾移植供体-受体组成。 在这里，我们建议测试其他遗传因素的作用。 因此，我们建议扩大 APOL1 的范围。 APOLLO 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 - 我们的提案解决了研究和临床方面现有的差异。 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代表性不足 研究表明，与非非洲血统患者相比，移植结果更差。 假设该人群中存在多种额外的遗传因素，这些因素会带来同种异体移植的风险 我们最近的工作清楚地表明，多基因背景和 APOL1 无关。 风险基因型对非洲血统个体的肾脏疾病风险有附加影响。 提议的全基因组多基因评分 (GPS) 结合多基因和 APOL1 风险，提供了实质性的帮助 现在迫切需要测试是否结合供体多基因。 此外，APOL1 风险改善了同种异体移植结果的预测。 全基因组遗传数据将促进对移植物产生影响的特定 APOL1 修饰因子的公正扫描 最后，APOLLO 研究为我们提供了进行遗传相容性的独特机会。 我们的目标是在 LIMS1 基因座上测试我们最初的“基因组碰撞”假设。 在这种情况下，携带基因破坏变异体的接受者在暴露于 然后我们将这一假设扩展到各种类型的遗传变异。 全基因组，包括破坏基因的拷贝数变异、预测的功能丧失变异，甚至 我们的发现研究中的任何积极发现都将在以下测试中进行验证： iGeneTRAiN 联盟的祖先多元化的国际研究团队由我们经验丰富的研究人员组成。 来自人类遗传学、精准医学、肾移植流行病学和统计学等领域 成功合作和执行涉及数千人的基因研究的记录。 我们相信这一提议将挑战现有的肾移植临床范式，我们的专家 团队处于领导这项工作的理想位置。