An Integrative Genomic Approach to APOL1-Associated Nephropathy.

描述（由申请方提供）：非裔美国人常见肾脏疾病（包括高血压所致）的发病率显著高于白人。载脂蛋白L1基因（APOL 1）变异体频率的种族差异是造成这些差异的原因。APOL 1风险变异在非洲裔美国人中的频率很高，因为一个拷贝可以保护人们免受导致非洲昏睡病的寄生虫的侵害，非洲昏睡病是一种潜在的致命疾病。大约10%的非洲裔美国人遗传了两个APOL 1风险变体的拷贝，使他们患肾脏疾病的风险增加了10倍。APOL 1基因变异导致肾脏疾病的机制尚不清楚。该申请旨在确定APOL 1基因变异如何导致肾脏疾病，这些信息可能会产生更有效的治疗方法。包括严格控制血压在内的现有疗法效果令人失望。我们建议确定：（1）肾细胞中APOL 1基因的变异是否直接导致细胞功能障碍并导致肾脏疾病，和/或（2）异常循环ApoL 1蛋白（高密度脂蛋白[HDL]结合或无脂）是否导致肾脏疾病。为了探索机制1，将在具有和不具有APOL 1风险变体的非裔美国人的肾细胞中检查基因表达谱，以基于细胞的APOL 1特异性遗传组成来确定哪些基因和基因途径过度表达（上调）或表达不足（下调）。为了探索机制2，将基于个体的遗传组成检查循环ApoL 1蛋白与HDL的结合模式和量。肾细胞将在体外暴露于正常和风险ApoL 1蛋白，以确定风险变体蛋白是否对细胞有毒以及这种毒性如何表现。基于这些研究，可以在表达正常和变体APOL 1的转基因小鼠中进行额外的分析，以评估ApoL 1蛋白的肾脏效应和体内代谢。我们还将尝试通过对周围染色体区域进行深度测序来识别APOL 1基因中未检测到的肾脏疾病风险变体。这些实验可能会确定APOL 1基因变异导致非糖尿病肾病的机制，并有助于找到治疗这种严重影响非裔美国人社区的毁灭性疾病的方法。

DESCRIPTION (provided by applicant): The incidence rates of common forms of kidney disease including that attributed to hypertension are significantly higher in African Americans, relative to Caucasians. Racial differences in the frequency of Apolipoprotein L1 gene (APOL1) variants are now known to account for these differences. APOL1 risk variants rose to high frequency in African Americans since one copy protects from the parasite that causes African sleeping sickness, a potentially fatal disease. Approximately 10% of African Americans inherit two copies of APOL1 risk variants, placing them at a ten-fold increased risk for kidney disease. The mechanism whereby APOL1 gene variants contribute to kidney disease is unknown. This application proposes to determine how APOL1 gene variants contribute to kidney disease, information likely to yield more effective therapies. Existing therapies including strict blood pressure control have had disappointing results. We propose to determine whether: (1) variation in the APOL1 gene in kidney cells directly leads to cell dysfunction with resultant kidney disease, and/or (2) abnormal circulating ApoL1 proteins (high density lipoprotein [HDL] bound or lipid-free) lead to kidney disease. To explore mechanism 1, gene expression profiles will be examined in kidney cells from African Americans with and without APOL1 risk variants to determine which genes and gene pathways are over expressed (turned up) or under expressed (turned down), based upon the APOL1- specific genetic make-up of the cells. To explore mechanism 2, the amount and binding patterns of circulating ApoL1 proteins to HDL will be examined based upon an individual's genetic make- up. Kidney cells will be exposed to normal and risk ApoL1 proteins in vitro to determine whether risk variant proteins are toxic to cells and how this toxicity manifests. Based on these studies, additional analyses may be conducted in transgenic mice expressing normal and variant APOL1 to assess renal effects and in vivo metabolism of ApoL1 proteins. We will also attempt to identify undetected kidney disease risk variants in the APOL1 gene by deeply sequencing the surrounding chromosomal region. These experiments are likely to determine the mechanisms whereby APOL1 gene variants lead to non-diabetic kidney disease and assist in finding a cure for this devastating disease disproportionately impacting the African American community.