Genetics of Renal Disease in African Americans

慢性肾脏疾病影响着2600多万美国人，经常导致需要透析或肾移植的肾衰竭。每年有超过10万人患上肾衰竭，近50万人接受透析或肾脏移植，每年的费用为300亿美元。肾功能衰竭需要透析或肾脏置换才能存活的三个主要原因是2型糖尿病、高血压和肾小球硬化。非洲裔美国人患终末期肾病(ESRD)的可能性是白人的3-4倍。FSGS是成人原发性肾病综合征的主要原因，也是儿童终末期肾病(ESRD)的主要原因。FSGS代表一种综合征，包括特发性变异和与肾单位数量减少、高血压和HIV-1感染相关的变异。非洲裔美国人患特发性FSGS的风险是四倍，HIV相关FSGS，也称为HIV相关肾病(HIVAN)的风险增加了50到70倍。HIVAN是导致非裔美国成年男性肾衰竭的第三大原因。在NIDDK肾脏病科的合作下，从13个校外地点招募了患者。这项研究包括经活检证实的散发性FSGS或HIV-1相关肾病(HIVAN)病例和919名捐赠者对照。超过60%的终末期肾病与糖尿病和高血压有关，约30%与肾小球疾病有关，主要由FSGS引起。我们还开展了合作，研究宿主遗传因素在其他肾脏疾病病因(例如，镰状细胞性贫血肾炎、先兆子痫、狼疮、糖尿病和高血压)中的作用。一项正在进行的主要研究是确定参加非裔美国人肾脏疾病和高血压(AASK)试验的高血压非裔美国人蛋白尿和终末期肾病(ESRD)的遗传预测因素。足细胞中表达的结构蛋白被认为在影响肾脏液压流动和蛋白质从血浆间隙进入尿液间隙的过程中发挥关键作用。足细胞表达的结构基因突变与常染色体隐性和显性孟德尔局灶性节段性肾小球硬化有关，通常发病较早，但相同基因的变异与特发性FSGS发病年龄一般较晚无关。我们最近报道，携带Myh9的Chr 22区域的风险等位基因与FSGS、HIVAN和非糖尿病终末期肾病密切相关。然而，即使经过广泛的搜索，也没有发现因果等位基因。成就最近选择的22号染色体上含有Myh9和APOL1的区域：2008年，我们在Chr 22上发现了一个区域，与艾滋病毒相关性肾病以及其他严重形式的肾脏疾病的风险增加有关。肾脏风险等位基因在非裔美国人中很常见，但在欧洲人中很少见，因此为重大的健康差异提供了遗传基础。使用来自人类基因组多样性小组(HGDP)的DNA样本，我们发现Chr 22Myh9区域最近在尼日利亚伊巴丹的约鲁巴被选择，但在其他非洲群体中没有。我们推测，Myh9肾脏风险等位基因可能跟踪邻近APOL1基因的变异。APOL1能裂解布氏锥虫，但不能裂解罗氏锥体或冈比亚锥体。都是T.B.罗德西恩斯和冈比亚锥虫编码一种解除APOL1的胰酶溶解活性的因子。在一项国际合作中，我们使用种群方法和1000基因组计划的结果来鉴定APOL1基因的两个突变，这两个突变与特发性FSGS和非糖尿病ESRD(OR 15-40)在隐性模型中密切相关。APOL1距离Myh9只有14kb，由于最近西非人对这些等位基因的选择，Myh9和APOL1风险等位基因出现在相同的单倍型上。血浆有效地溶解了结核分枝杆菌。即使滴度高于1000，这表明携带一种或另一种胰酶突变的供体血浆可能被证明是治疗结核分枝杆菌的一种经济有效的方法。罗德塞恩斯。虽然APOL1突变在携带者中提供了对致命病原体的保护，但具有胰酶溶解突变的纯合子和复杂杂合子的个体更容易患肾脏疾病。对特发性FSGS和归因于高血压的终末期肾脏疾病的影响非常强烈。我们已经证明，Myh9风险等位基因与以肾小球损伤为特征的一系列肾脏疾病相关，OR在4-7范围内。APOL1突变具有更强的影响，使其成为迄今发现的常见疾病的最强风险因素。通过揭示特定的基因病变是几乎所有FSGS的基础，以及非糖尿病ESRD的很大一部分，这些发现从根本上改变了对这些疾病的理解，并揭示了重大健康差距的基础。

Chronic kidney disease, affecting over 26 million Americans, frequently leads to kidney failure requiring either dialysis or kidney transplant. Each year more than 100,000 individuals develop kidney failure and nearly 500,000 receive dialysis or kidney transplants at an annual cost of $30 billion dollars. The three leading causes of kidney failure requiring dialysis or kidney replacement for survival are type 2 diabetes, hypertension, and glomerulosclerosis. African Americans are 3-4 times more likely to develop end stage renal disease (ESRD) compared to their white counterparts. FSGS is the leading cause of primary nephritic syndrome in adults and the leading cause of end-stage renal disease (ESRD) in children. FSGS represents a syndrome that includes idiopathic variants and variants associated with reduced nephron numbers, hypertension, and HIV-1 infection. African-Americans are at a four-fold risk of developing idiopathic FSGS, and at a 50 to 70-fold increased risk for HIV-associated FSGS, also known as HIV-associated nephropathy (HIVAN). HIVAN is the third leading cause of kidney failure in African American adult men. In collaboration with the Kidney Disease Section, NIDDK, patients have been enrolled from 13 extramural sites. The study comprises biopsy-proven sporadic FSGS or HIV-1-associated nephropathy (HIVAN) cases with biopsy-proven collapsing glomerulosclerosis and 919 donor controls. More than 60% of end stage kidney disease is associated with diabetes and hypertension, and approximately 30% with glomerulopathies, mainly due to FSGS. We have have also entered into collaborations to investigate the role of host genetic factors in other etiologies of kidney disease (e.g., sickle cell anemia nephritis, pre-elampsia, lupus, diabetes, and hypertension). A major on-going investigation is to determine genetic predictors of proteinuria and endstage renal disease (ESRD) in African Americans with hypertension enrolled in the African American Kidney Disease and Hypertension (AASK) Trial. Structural proteins expressed in podocytes are postulated to play a critical role in influencing hydraulic flow and protein exit from the plasma space into the urinary space in the kidney. Mutations in podocyte-expressed structural genes have been associated with both autosomal recessive and dominant Mendelian focal segmental glomerulosclerosis, generally with early onset, but variants in the same genes have not been associated with idiopathic FSGS with generally later age of onset. We recently reported that risk alleles in the Chr 22 region harboring MYH9 were strongly associated with FSGS, HIVAN, and non-diabetic end stage renal disease. However, even after extensive searching, causal alleles were not identified. Accomplishments Chromosome 22 region harboring MYH9 and APOL1 under recent selection: In 2008 we identified a region on Chr 22 associated with increased risk of HIV-associated nephropathy as well as other severe forms of kidney disease. The renal risk alleles were frequent in African Americans but rare in Europeans thereby providing a genetic basis for a major health disparity. Using DNA samples from the Human Genome Diversity Panel (HGDP) we showed that the Chr 22 MYH9 region was under recent selection in Yoruba from Ibadan, Nigeria but not in other African populations. We hypothesized that the MYH9 renal risk alleles might tracking variants in the adjacent APOL1 gene. APOL1 lyses Trypanosome brucei brucei but not Trypanosome b. rhodensiense or gambiense. Both T.b. rhodesiense and T.b.gambiense encode a factor that disarms the trypanolytic activity of APOL1. In an international collaboration, we used population approaches and the results from the 1000 Genomes Project to identify two mutations in the APOL1 gene that were strongly associated with idiopathic FSGS and non-diabetic ESRD (OR 15-40) in a recessive model. APOL1 is only 14 kb from MYH9 and the MYH9 and APOL1 risk alleles occur on the same haplotypes due to the recent selection in west Africans on these alleles. The plasma effectively lysed T.b. rhodesiense even at titers greater than 1000 suggesting that donor plasma harboring one or the other trypanolytic mutation might prove to be a cost-effective treatment for T.b. rhodesiense. While APOL1 mutations provide protection against a lethal pathogen in carriers individuals who are homozygotes and complex heterozygotes for the trypanolytic mutations are more vulnerable to kidney disease. The effects are extremely strong for idiopathic FSGS and end stage renal disease attributed to hypertension. We have shown that MYH9 risk alleles are associated with a broad range of kidney disease characterized by glomerular injury with OR in the 4-7 range. The APOL1 mutations have even stronger effects, making these the strongest risk factors discovered to date for a common disease. By revealing that a specific genetic lesion is fundamental to almost all FSGS, and a significant fraction of non-diabetic ESRD, these findings have fundamentally changed the understanding of these diseases, and uncovered the basis of a major health disparity.