Non-APOL1 genetic factors and kidney transplant outcomes

摘要 这是一项前瞻性APOLLO（APOL 1长期肾移植结局）的辅助研究 2,800对肾移植供受者队列。母研究旨在测试APOL 1风险的影响 基因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， APOL 1以外的其他基因在决定同种异体移植物预后方面的作用。因此，我们建议扩大 APOLLO研究为所有2，800名供体生成高质量的全基因组SNP和外显子组序列数据- 由网络注册的收件人对。我们的建议解决了研究和临床方面存在的差距， 由于患有终末期肾病的非洲血统患者目前在遗传学上代表性不足， 与非非洲血统的患者相比，他们的移植结果更差。我们的总体 一种假设是，在这一人群中有多种额外的遗传因素传递了同种异体移植的风险 与APOL 1无关的损失。我们最近的研究清楚地表明，多基因背景和APOL 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累加效应。我们新 建议的全基因组多基因评分（GPS）结合多基因和APOL 1风险提供了实质性的 改善肾脏疾病的预测。现在迫切需要测试是否结合供体多基因 APOL 1风险改善了对同种异体移植物结局的预测。此外，我们提出的新一代 全基因组遗传数据将有助于无偏扫描特定的APOL 1修饰剂， 生存最后，APOLLO研究为我们提供了一个独特的机会， 扫描完整的捐赠者-接受者配对。我们的目标是在LIMS 1位点测试我们最初的“基因组碰撞”假设 在这种情况下，携带基因破坏变异体的受体在暴露于一种 表达完整基因产物的移植物。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，包括基因破坏拷贝数变异，预测的功能丧失变异，甚至 错义变体。我们的发现研究中的任何积极发现都将在 iGeneTRAiN联盟的血统多样的国际队列。我们经验丰富的调查团队 来自人类遗传学、精准医学、肾移植流行病学和统计学领域的专家们， 成功合作和执行涉及数千名参与者的遗传研究的记录。 我们相信这一建议将挑战现有的肾移植临床模式，我们的专家 团队是领导这项工作的理想人选。

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.