Genetics of Renal Disease in African Americans

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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.