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 idiopathic variants and variants 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). A major on-going investigation is to determine genetic predictors of proteinuria and endstage renal disease (ESRD) in African Americans with hypertension enrolled in the African American Kidney Disease and Hypertension (AASK) Trial. 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. Mutations in podocyte-expressed structural genes have been associated with both autosomal recessive and dominant Mendelian focal segmental glomerulosclerosis, generally with early onset, but variants in the same genes have not been associated with idiopathic FSGS with generally later age of onset. We recently reported that risk alleles in the Chr 22 region harboring MYH9 were strongly associated with FSGS, HIVAN, and non-diabetic end stage renal disease. However, even after extensive searching, causal alleles were not identified. Accomplishments Chromosome 22 region harboring MYH9 and APOL1 under recent selection: In 2008 we identified a region on Chr 22 associated with increased risk of HIV-associated nephropathy as well as other severe forms of kidney disease. The renal risk alleles were frequent in African Americans but rare in Europeans thereby providing a genetic basis for a major health disparity. Using DNA samples from the Human Genome Diversity Panel (HGDP) we showed that the Chr 22 MYH9 region was under recent selection in Yoruba from Ibadan, Nigeria but not in other African populations. We hypothesized that the MYH9 renal risk alleles might tracking variants in the adjacent APOL1 gene. APOL1 lyses Trypanosome brucei brucei but not Trypanosome b. rhodensiense or gambiense. Both T.b. rhodesiense and T.b.gambiense encode a factor that disarms the trypanolytic activity of APOL1. In an international collaboration, we used population approaches and the results from the 1000 Genomes Project to identify two mutations in the APOL1 gene that were strongly associated with idiopathic FSGS and non-diabetic ESRD (OR 15-40) in a recessive model. APOL1 is only 14 kb from MYH9 and the MYH9 and APOL1 risk alleles occur on the same haplotypes due to the recent selection in west Africans on these alleles. The plasma effectively lysed T.b. rhodesiense even at titers greater than 1000 suggesting that donor plasma harboring one or the other trypanolytic mutation might prove to be a cost-effective treatment for T.b. rhodesiense. While APOL1 mutations provide protection against a lethal pathogen in carriers individuals who are homozygotes and complex heterozygotes for the trypanolytic mutations are more vulnerable to kidney disease. The effects are extremely strong for idiopathic FSGS and end stage renal disease attributed to hypertension. We have shown that MYH9 risk alleles are associated with a broad range of kidney disease characterized by glomerular injury with OR in the 4-7 range. The APOL1 mutations have even stronger effects, making these the strongest risk factors discovered to date for a common disease. By revealing that a specific genetic lesion is fundamental to almost all FSGS, and a significant fraction of non-diabetic ESRD, these findings have fundamentally changed the understanding of these diseases, and uncovered the basis of a major health disparity.
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