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.
| Franceschini, Nora; North, Kari E; Kopp, Jeffrey B et al. (2006) NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review. Genet Med 8:63-75 |
| Kopp, Jeffrey B; Winkler, Cheryl (2003) HIV-associated nephropathy in African Americans. Kidney Int Suppl :S43-9 |
