Genetics of Renal Disease in African Americans

非裔美国人肾病遗传学

• 批准号: 7965194
• 负责人: Cheryl Winkler
• 金额: $ 97.83万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965194
• 关键词: AIDS-Associated Nephropathy; Accounting; Admixture; Adult; Affect; African; African American; Alleles; American; Amino Acids; Arginine; Biopsy; Bowman' s space; Child; Childhood; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 22; Chronic; Chronic Kidney Failure; Cicatrix; Clinical; Codon Nucleotides; Collaborations; Counseling; DNA; Development; Diabetes Mellitus; Dialysis procedure; Disease; Drug Delivery Systems; End stage renal failure; Enrollment; Environmental Risk Factor; Essential Hypertension; Etiology; European; Exons; Extramural Activities; Family; Focal Segmental Glomerulosclerosis; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Screening; Genetic Variation; Genomics; Glutamine; Growth; HIV Infections; HIV-1; Haplotypes; Homozygote; Hypertension; Impairment; Incidence; Individual; Infection; Injury; Introns; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Lead; Linkage Disequilibrium; Lupus; Maps; Medicine; Mus; Mutation; NPHS2 protein; National Institute of Diabetes and Digestive and Kidney Diseases; Nephritis; Nephrons; Nephrosclerosis; Non-Insulin-Dependent Diabetes Mellitus; Orthologous Gene; Patients; Persons; Plasma; Play; Point Mutation; Population; Positioning Attribute; Predisposition; Protein Isoforms; Proteins; Proteinuria; Public Health; Publishing; RNA Splicing; Risk; Risk Factors; Risk Reduction Behavior; Role; Sickle Cell Anemia; Signal Transduction; Site; Staging; Structural Protein; Susceptibility Gene; Syndrome; Time; Transcript; Variant; Wilms Tumor Genes; Wit; base; case control; cost; design; diabetic; genetic variant; glomerulosclerosis; health disparity; hypertension control; men; modifiable risk; mouse model; nephrogenesis; non-diabetic; podocyte; population based; positional cloning; prevent

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 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 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). 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 small fraction of FSGS disease incidence. Accomplishments Because of the increased risk of chronic and end stage kidney disease in African Americans, we hypothesized that the increased predilection for kidney disease among African-descent individuals is due to the presence of one or more causal alleles more frequent in individuals with African ancestry. Using mapping by admixture disequilibrium (MALD) followed by fine mapping, we recently identified MYH9 on Chromosome 22 as a main effect gene for sporadic and HIV-1-related FSGS and 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. 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 explained the excess burden in African Americans for these major kidney diseases and provide a genetic basis for a major USA and global health disparity. We have continued to examine the role of MYH9 risk variants in other forms of kidney diseases and in larger study groups to more precisely assess risk. In collaborative studies we have shown and published that MYH9 is a predictor of kidney failure historically attributable to hypertension (OR range 1.5-3) and to kidney failure in a setting of diabetes (OR range 1.2-1.4). The results of these studies indicate that MYH9 underlies a portion of hypertensive and diabetic ESRD in African Americans. This suggests that a subset of African Americans with type 2 diabetes and hypertension co-incident with nephropathy have primary MYH9-related kidney disease (e.g. FSGS or global glomerulosclerosis). Before the discovery of MYH9 as a renal susceptibility gene, it was widely held that essential hypertension was the inciting cause of nephrosclerosis and progression to ESRD, but this new evidence suggests that at least part of hypertension-associated renal failure may be due underlying MYH9-related kidney disease. This also explains, in part, why intensive treatment to control hypertension has proven ineffective in hypertensive African Americans. This also provides an explanation for why kidney disease with disparate etiologies (e.g., diabetic, hypertension, HIV infection) clustered in families. To identify the functional genetic variation we have used a two stage re-sequencing strategy. In the first stage we re-sequenced MYH9 exons from 19 persons carrying risk haplotypes but failed to identify codon-changing mutations that could account for the associations with kidney disease. In the next stage we re-sequenced genomic DNA from both introns and exons from 39 individuals carrying MYH9 risk protective and susceptible risk haplotypes. Again we failed to discover codon-changing mutations that could account for the signal. These results have led us to focus our efforts on transcript expression differences in either the levels of transcripts expressed or in splice isoforms. Dense mapping of <i>MYH9</i> is now being performed to identify the causal functional variation responsible for podocyte impairment predisposing to kidney disease. 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.

慢性肾脏疾病影响着2600多万美国人，经常导致肾衰竭，需要透析或肾移植。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，每年花费300亿美元。肾衰竭的三个主要原因需要透析或肾脏替代生存是2型糖尿病，高血压和肾小球硬化。非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是一种包括特发性变异的综合征，与肾细胞数量减少、高血压和HIV-1感染有关。非洲裔美国人发生特发性FSGS的风险为4倍，发生hiv相关FSGS的风险为50 - 70倍，也称为hiv相关肾病（HIVAN）。hiv是非裔美国成年男性肾衰竭的第三大原因。在与NIDDK肾脏疾病科的合作下，从13个校外地点招募了患者。该研究包括活检证实的散发性FSGS或hiv -1相关肾病（HIV-1-associated nephropathy， HIVAN）伴塌陷性肾小球硬化病例和919例供体对照。超过60%的终末期肾病与糖尿病和高血压有关，约30%与肾小球病变有关，主要是由FSGS引起的。我们还开展了合作，研究宿主遗传因素在其他肾病病因中的作用（如镰状细胞性贫血肾炎、痫前期、狼疮、糖尿病和高血压）。足细胞中表达的结构蛋白被认为在影响水力流动和蛋白质从血浆空间进入肾脏尿空间的过程中起关键作用。NPHS2编码足细胞蛋白，这是一种只在肾小球足细胞上表达的蛋白。NPHS2基因的点突变导致podocin蛋白138位（R138Q）的氨基酸从精氨酸变为谷氨酰胺。这种多态性的纯合子会发展为儿童FSGS，但我们首次发现138Q携带者发生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。在一个有希望的FSGS小鼠模型中，PDSS2的小鼠同源物已被证明在肾脏疾病中发挥作用。我们发现，在欧美研究组中，具有特定单倍型的个体患FSGS的几率增加了5-6倍。Wilms肿瘤基因（WT-1）对肾发生和性腺激素的生长很重要，WT-1的突变导致肾小球瘢痕形成。WT-1基因和相邻的WT-1基因的变异被证明是FSGS的危险因素。仍然有理由相信，其他基因和/或环境因素会影响FSGS的易感性和坍缩性肾小球病，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。由于非裔美国人患慢性和终末期肾脏疾病的风险增加，我们假设非洲裔个体对肾脏疾病的偏好增加是由于非洲裔个体中存在一个或多个更常见的因果等位基因。利用混合不平衡定位（MALD）和精细定位，我们最近发现22号染色体上的MYH9是非洲裔美国人散发性和hiv -1相关的FSGS和非糖尿病肾病的主要影响基因。在两项研究中，我们发现一个基因位点MYH9在很大程度上解释了非洲裔美国人散发性、hiv相关的FSGS塌陷和高血压性肾衰竭的风险增加，这表明这些形式的肾脏疾病具有共同的遗传病因。最强单倍型和风险等位基因的频率在非洲裔美国人中为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对这些主要肾脏疾病的过度负担，并为美国和全球的主要健康差异提供了遗传基础。我们继续研究MYH9风险变异在其他形式肾脏疾病中的作用，并在更大的研究组中更精确地评估风险。在合作研究中，我们已经证明并发表了MYH9是历史上由高血压（OR范围1.5-3）和糖尿病（OR范围1.2-1.4）引起的肾衰竭的预测因子。这些研究结果表明，MYH9是非裔美国人高血压和糖尿病ESRD的一部分原因。这表明，一部分2型糖尿病和高血压合并肾病的非裔美国人有原发性myh9相关肾脏疾病（如FSGS或全局肾小球硬化）。在MYH9作为肾脏易感基因被发现之前，人们普遍认为原发性高血压是肾硬化和发展为ESRD的诱因，但这一新的证据表明，至少部分高血压相关的肾功能衰竭可能是由于潜在的MYH9相关肾脏疾病。这也部分解释了为什么强化治疗控制高血压对非裔美国人无效。这也解释了为什么不同病因的肾脏疾病（如糖尿病、高血压、艾滋病毒感染）在家庭中聚集。为了确定功能性遗传变异，我们使用了两阶段重测序策略。在第一阶段，我们对19名携带风险单倍型的人的MYH9外显子进行了重新测序，但未能确定可能与肾脏疾病相关的密码子改变突变。在下一阶段，我们对39名携带MYH9风险保护型和易感风险单倍型的个体的内含子和外显子的基因组DNA进行了重新测序。我们又一次没能发现密码子改变突变来解释这个信号。这些结果使我们将重点放在转录本表达水平或剪接异构体的转录本表达差异上。目前正在进行&lt；i>MYH9</i&gt；的密集定位，以确定导致易患肾脏疾病的足细胞损伤的因果功能变异。预计这些发现将导致更有针对性的治疗慢性肾脏疾病的方法，以防止或延缓肾衰竭的进展。我们还期望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较高的个体，并为基因脆弱的个体提供可改变的风险降低行为咨询。虽然不是每个携带MYH9风险等位基因的人都会患上慢性肾病，但这些人患病的可能性增加了100-500%。