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 and APOL1 were strongly associated with FSGS, HIVAN, and non-diabetic end stage renal disease. In highly collaborative studies we have refined the association of APOL1 structural variants with FSGS phenotypes and extended the association for the first time to HIVAN. The APOL1 associations with CKD and ESRD are among the strongest and most frequent observed for a common disease. These series of studies have important implications for translational research and for personalized medicine. Accomplishments In a collaborative study we recently reported that trypanolytic mutations in APOL1, encoding apolipoproteinL1, were associated with FSGS and ESKD in African Americans;their role in HIV-associated nephropathy (HIVAN) was not investigated. We studied patients with biopsy proven idiopathic focal segmental glomerulosclerosis (FSGS) and HIVAN to define more precisely the genetic risk and to determine whether APOL1-associated FSGS has a distinct clinical phenotype. We determined APOL1 genotypes for 271 African American FSGS and HIVAN cases, 168 European American FSGS cases and 939 control subjects. In a recessive model, APOL1 variants were associated with 20-fold increased risk for FSGS and 40-fold increased risk for HIVAN compared to subjects without the risk alleles. For FSGS associated with two APOL1 risk alleles, compared to other FSGS patients, onset age was approximately a decade earlier and progression to ESKD was faster. Two APOL1 risk alleles confer an attributable risk of 67% for FSGS and HIVAN and an explained fraction of 18% for FSGS and 35% for HIVAN;this is similar to the risk conferred by smoking for small-lung-cell carcinoma. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS and those with untreated HIV disease have a 50% risk for developing HIVAN. A survey of world populations indicates that the APOL1 kidney risk alleles are present only on African chromosomes. These data add to the evidence base required to define the role for APOL1 genetic testing in personalized medicine. We have also investigated the role of APOL1 and MYH9 variation in diabetic and non-diabetic kidney disease. In spite of intensive blood pressure control with angiotensin converting enzyme inhibitors in subjects enrolled in the AASK trial, there was no significant effect on renal progression endpoints. Coding variants in APOL1 gene that are strongly associated with non-diabetic nephropathy in African Americans were evaluated for association with hypertension-attributed nephropathy in 675 AASK participants and with clinical outcomes and 618 African American controls, including progressive renal function loss. To determine AASK participants (675) and 618 AA non-nephropathy controls were genotyped for the APOL1 G1 and G2 coding variants. In a recessive model, APOL1 risk variants were significantly associated with kidney disease in all AASK cases vs. controls. (OR 2.57;p=1.4E-8). We also found that APOL1 variants were associated with higher baseline urine protein/creatinine ratios (OR 6.29;p=2.6E-14) and higher serum creatinine during follow-up (OR 4.61;p=5.6E-15). Kidney disease in AASK participants was associated with APOL1 risk variants, particularly for those with baseline proteinuria. This study suggests that APOL1 variants may initiate chronic kidney disease previously attributed to hypertension. We also showed that chromosome 22 variants may interact with other genes. Many African Americans with type 2 diabetes (T2D), the leading cause of CKD and ESKD, have non-diabetic kidney disease, potentially masking detection of diabetic nephropathy genes. In a collaborative study with NIDDK and Wake Forest University, genome-wide association analyses were performed in 966 African Americans with T2D nephropathy (T2DN) and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for chromosome (c) 22 MYH9 and APOL1 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9. This finding was replicated in 1323 African American T2DN cases and NDNN controls. FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (interaction p-value = 9.3E-7). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes, but not in homozygotes for MYH9 E1 risk haplotype. FRMD3 SNPS were associated with T2DN, and not type 2 diabetes, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes.
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