APOL1 variants: Understanding the basis of disparities in rates of kidney disease

摘要 超过50万美国人患有终末期肾病(ESRD)。非裔美国人发育出肾脏 失败率是欧洲美国人的4-5倍。最近，我们发现了两个编码序列 载脂蛋白L1(APOL1)的变异在这一重大健康差距中占很大比例。APOL1 肾脏疾病的变异对多种不同类型的肾脏疾病有重大影响，包括 高血压相关性终末期肾病、局灶节段性肾小球硬化(FSGS)和HIV相关性肾病 (HIVAN)风险遗传是隐性的：具有两个变异的APOL1等位基因的个体的风险增加了7-30倍 有患肾脏疾病的风险。我们预测，超过350万非裔美国人患有高危APOL1 基因分型。两个风险等位基因的存在并不会导致所有个体的肾脏疾病，这表明 其他遗传和环境因素也是重要的影响因素。理解为什么有些人有 高危基因会患上肾脏疾病，而其他高危基因不会改善风险分层，并可能说明 最容易接受治疗的途径。因此，我们建议：目标1：确定更多的基因 APOL1基因座的修饰物。我们的数据表明，APOL1肾病风险变异体是- 功能等位基因。由于并不是所有具有两个风险等位基因的个体都会患上疾病，其他局部多态可能 调节APOL1的表达，调节致病的APOL1编码突变的效果。我们会 确定可能改变APOL1基因表达的结构变体，并测试它们对APOL1基因外显性的影响 两个致病等位基因。我们将测试转录因子和microRNA结合的多态 位点会影响这些APOL1风险等位基因的外显性。目标2：寻找APOL1的上位修饰语 洞察力。APOL1肾病风险变异体在非洲的频率增加，至少部分是因为它们 提供了对锥虫的保护。我们假设额外的遗传基因座同时 从主要的编码风险等位基因中筛选出对肾脏损伤具有保护作用的基因，并且 在与欧洲人打成一片后，这些基因座可能已经减少。在这里，我们将进行全基因组筛选 用于可能预防或加重APOL1变异引起的肾损伤的基因多态性。我们将确定 与野生型和编码变异体APOL1有差异结合的蛋白质，因为这些结合伙伴可能调节 由风险变种引起的伤害。目的3：鉴定APOL1介导的肾脏的生化修饰物 疾病。在设定其他危险因素时，APOL1肾病风险变异体可能是最有害的。 在这里，我们探索两个重要的因素如何与APOL1基因相互作用而导致肾脏疾病。 维生素D被认为对肾脏损伤具有保护作用，而某些脂类可能会促进损伤。我们 问这些分子是否在体外改变了APOL1的生物学，以及这些介体的生化水平 预测哪些携带APOL1风险基因的个体有可能患上肾脏疾病。

SUMMARY More than 500,000 Americans suffer from end-stage renal disease (ESRD). African Americans develop kidney failure at rates 4-5 fold higher than European Americans. Recently, we discovered two coding sequence variants in ApolipoproteinL1 (APOL1) that account for a large proportion of this major health disparity. APOL1 kidney disease variants have a major impact on multiple different types of kidney disease including hypertension-associated ESRD, focal segmental glomerulosclerosis (FSGS), and HIV-associated nephropathy (HIVAN). Risk inheritance is recessive: individuals with two variant APOL1 alleles have a 7-30 fold increased risk for kidney disease. We predict that more than 3.5 million African Americans have the high risk APOL1 genotype. The presence of two risk alleles does not lead to kidney disease in all individuals, indicating that other genetic and environmental factors are important modifiers. Understanding why some individuals with the high-risk genotype develop kidney disease while others do not will improve risk stratification and may illuminate the pathways most amenable to therapy. We therefore propose to: Aim 1: Identify additional genetic modifiers at the APOL1 gene locus. Our data suggest that APOL1 kidney disease risk variants are gain-of- function alleles. Since not all individuals with two risk alleles develop disease, other local polymorphisms may regulate expression of APOL1, modulating the effect of the disease-causing APOL1 coding mutations. We will define structural variants that may alter APOL1 gene expression, and test their effects on the penetrance of the two disease-causing alleles. We will test whether polymorphisms in transcription factor and microRNA binding sites affect the penetrance of these APOL1 risk alleles. Aim 2: Find epistatic modifiers of APOL1 penetrance. The APOL1 renal risk variants increased in frequency in Africa, at least in part, because they provided protection against trypanosomes. We hypothesize that additional genetic loci were simultaneously selected that protect against renal injury from the major coding risk alleles, and that the protective effect of these loci may have diminished after admixture with Europeans. Here, we will perform a genome-wide screen for polymorphisms that may protect against or exacerbate APOL1 variant-induced renal injury. We will identify proteins that bind differentially to wild type and coding variant ApoL1, as these binding partners may modulate injury caused by the risk variants. Aim 3: Identify biochemical modifiers of APOL1-mediated renal disease. ApoL1 kidney disease risk variants may be most deleterious in the setting of additional risk factors. Here, we explore how two important factors may interact with APOL1 genotype to cause renal disease. Vitamin D is believed to be protective against renal injury, while certain lipid profiles may promote injury. We ask whether these molecules alter APOL1 biology in vitro, and whether biochemical levels of these mediators predict which individuals with the APOL1 risk genotype are likely to develop kidney disease.