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。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，并与肾单位数量减少、高血压和HIV-1感染相关。非洲裔美国人患特发性FSGS的风险是前者的四倍，而与HIV相关的FSGS的风险是后者的18倍。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379例特发性或HIV-1相关的FSGS病例和919名捐赠者对照。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。NPHS2编码Podocin，这是一种仅在肾小球足细胞上表达的蛋白质。NPHS2基因点突变导致Podocin蛋白第138位(R138Q)的氨基酸从精氨酸变为谷氨酰胺。这种多态的纯合子会导致儿童FSGS，但我们首次表明，138Q携带者患FSGS的风险增加了5-6倍。在合作研究中，我们研究了PDSS2基因突变在FSGS易感性中的可能作用。PDSS2的小鼠同源基因已被证明在FSGS的小鼠模型中在肾脏疾病中发挥作用。我们发现，在欧美研究小组中，具有特定单倍型的个体患FSGS的机会增加了5-6倍。肾母细胞瘤基因(WT-1)在肾发生和性腺激素生长中起重要作用，WT-1基因突变导致肾小球瘢痕形成。WT-1基因和邻近的WIT-1基因变异被证明是FSGS的危险因素。仍然有理由相信，额外的基因和/或环境因素影响FSGS和塌陷性肾小球疾病的易感性，因为这些变异等位基因只解释了FSGS疾病发病率的一小部分。利用杂交不平衡作图(MALD)，我们在22号染色体上定位了一个与散发性和HIV-1相关的FSGS密切相关的染色体区域。我们发现Myh9是非裔美国人非糖尿病肾病的主要危险因素。在两项研究中，我们表明一个名为Myh9的基因位点解释了非裔美国人零星的、HIV相关的FSGS崩溃和高血压肾衰竭风险增加的很大一部分原因，这表明这些形式的肾脏疾病有共同的遗传病因。然而，这种关联并没有延伸到糖尿病肾功能衰竭，这首次表明导致肾脏损害的遗传因素和细胞机制在高血压和糖尿病肾脏疾病之间存在差异。最强的单倍型和风险等位基因在非裔美国人中的频率为60%或更高，在欧洲裔美国人中不到4%。我们的发现在很大程度上解释了非裔美国人在这些常见的非糖尿病肾脏疾病上的过度负担。预计这些发现将导致治疗慢性肾脏疾病的更有针对性的方法，以防止或延缓进展为肾衰竭。我们还预计，这一发现将对公众健康产生重大影响--基因筛查将有助于识别肾脏疾病风险更高的个人，并在可改变的风险降低行为中为遗传脆弱的个人提供咨询。虽然不是每个携带Myh9风险等位基因的人都会患上慢性肾脏疾病，但在这些人中，患病的可能性增加了100%-500%。Myh9变异解释了非洲裔美国人和欧洲裔美国人之间FSGS风险差异的至少70%，甚至可能是100%。

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. 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 variants that are idiopathic and are associated with reduced nephron numbers, hypertension, and HIV-1 infection. African-Americans are at a four-fold risk of developing idiopathic FSGS, and at an 18-fold increased risk for HIV-associated FSGS. In collaboration with the Kidney Disease Section, NIDDK, patients have been enrolled from 13 extramural sites. The study is comprised of 379 cases of idiopathic or HIV-1-associated FSGS cases and 919 donor controls. 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. NPHS2 encodes podocin, a protein expressed exclusively on the glomerular podocyte. A point mutation in the NPHS2 gene causes an amino acid change from arginine to glutamine at position 138 (R138Q) in the podocin protein. Homozygotes for this polymorphism develop childhood FSGS, but we have shown for the first time that 138Q carriers are at a 5-6 fold increased risk of developing FSGS. In collaborative study we have investigated the possible role of mutations in the PDSS2 gene in susceptibility to FSGS. The mouse ortholog of PDSS2 has been shown to play a role in kidney disease in a promising mouse model for FSGS. We discovered that individuals in the European American study group with a specific haplotype have a 5-6 fold increased chance of developing FSGS. The Wilms' tumor gene (WT-1) is important for nephrogenesis and gonadol growth and mutations in WT-1 lead to glomerular scarring. Variants in the WT-1 gene and the adjacent WIT-1 gene were shown to be risk factors for FSGS. There is still reason to believe that additional genes and/or environmental factors affect susceptibility to FSGS and collapsing glomerulopathy as these variant alleles explain only a fraction of FSGS disease incidence. Accomplishments Using mapping by admixture disequilibrium (MALD), we have located a chromosomal region on Chromosome 22 that is strongly associated with sporadic and HIV-1-related FSGS. We identified MYH9 as a major risk factor for nondiabetic kidney disease in African Americans. In two studies, we showed that a genetic locus, MYH9, explains much of the increased risk in African Americans for sporadic, HIV-associated collapsing FSGS and hypertensive kidney failure suggesting a shared genetic etiology for these forms of kidney disease. However, this association did not extend to diabetic kidney failure, suggesting for the first time that the genetic factors and cellular mechanisms leading to kidney damage differ between hypertensive and diabetic kidney diseases. The strongest haplotype and risk alleles have frequencies of 60% or more in African Americans and less than 4% in European Americans. Our finding substantially explains the excess burden in African Americans for these common nondiabetic kidney diseases. It is anticipated that these findings will lead to more targeted approaches for the treatment of chronic kidney disease to prevent or delay progression to kidney failure. We also expect that this finding will have a major impact on public health--genetic screening will be useful in identifying individuals at greater risk for kidney disease and in counseling genetically vulnerable individuals in modifiable risk reduction behaviors. While not everyone with MYH9 risk alleles will develop chronic kidney disease, the likelihood of disease is increased by 100-500% in these individuals. The MYH9 variants explain at least 70%, and possibly 100%, of the difference in risk of FSGS between African and European Americans.