Genetics of Renal Disease in African Americans

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，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的风险是正常人的4倍，患HIV相关FSGS的风险增加18倍。与NIDDK肾脏疾病科合作，从13个院外研究中心招募了患者。该研究包括379例特发性或HIV-1相关FSGS病例和919例供体对照。足细胞中表达的结构蛋白被假定在影响液压流和蛋白质从血浆空间进入肾脏中的尿空间中起关键作用。NPHS 2编码podocin，一种仅在肾小球足细胞上表达的蛋白质。NPHS 2基因的点突变导致podocin蛋白第138位（R138 Q）的氨基酸从精氨酸变为谷氨酰胺。这种多态性的纯合子发展儿童FSGS，但我们首次表明，138 Q携带者发展FSGS的风险增加5-6倍。在合作研究中，我们研究了PDSS 2基因突变在FSGS易感性中的可能作用。PDSS 2的小鼠直系同源物已被证明在FSGS的有希望的小鼠模型中在肾脏疾病中发挥作用。我们发现，具有特定单倍型的欧美研究组中的个体具有5-6倍增加的发展FSGS的机会。肾母细胞瘤基因（WT-1）对于肾发生和性腺生长是重要的，WT-1中的突变导致肾小球瘢痕形成。WT-1基因和邻近的WIT-1基因的变异被证明是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和塌陷性肾小球病的易感性，因为这些变异等位基因仅解释FSGS疾病发病率的一小部分。NPHS 2基因突变是儿童早期发病的类固醇耐药常染色体隐性FSGS的常见原因。我们检验了NPHS 2突变携带者发生散发性和HIV-1相关FSGS的风险增加的假设，发现罕见突变（R138 Q）携带者发生FSGS的可能性是普通人群的5倍，但总体而言，NPHS 2突变仅占成人发病FSGS的一小部分。这一发现很重要，因为它提供了R138 Q携带者风险增加的第一个证据，并表明类固醇耐药常染色体FSGS患者的家庭成员也可能有迟发性FSGS的风险。使用混合不平衡（MALD）作图，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。通过精细定位，我们已经将这种关联定位到一个单一的基因上，该基因使FSGS的风险增加了6到8倍。与欧洲血统的人相比，易感等位基因在非洲血统的人中更常见，这表明非洲裔美国人中许多形式的肾脏疾病的风险增加可能是由于该基因。

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 Mutations in the NPHS2 gene are a common cause of steroid resistant, autosomal recessive FSGS with early childhood onset. We tested the hypothesis that carriers of NPHS2 mutations would be at increased risk for sporadic and HIV-1-related FSGS and found that carriers of a rare mutation (R138Q) were 5-fold more likely to develop FSGS compared to the general population, but that overall, NPHS2 mutations accounted for only a small fraction of adult onset FSGS. This finding was important because it provides the first evidence that R138Q carriers are at increased risk and suggests that family members of patients with steroid resistant, autosomal FSGS may also be at risk for late onset FSGS. 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. By fine mapping we have localized the association to a single gene that increases risk of FSGS by 6 to 8-fold. The susceptible allele(s) are much more common in persons of African ancestry compared to those of European ancestry, suggesting that the increased risk of many forms of kidney disease in African Americans may be due to this gene.