BACKGROUND Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)

End stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans. This led to the hypothesis that susceptibility alleles for ESRD have a higher frequency in West African than European gene pool. We performed a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and demonstrated a highly significant association between excess African ancestry and non-diabetic ESRD (LOD 5.70) but not diabetic ESRD (LOD 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% credible interval 0.39 -0.63) compared to African ancestry. Multiple common SNPs (allele frequency ranging from 0.2 to 0.6) in the gene that encodes non-muscle myosin heavy chain type II isoform A (MYH9) were associated with 2-4 times greater risk of non-diabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.End stage renal disease (ESRD) is the near-total loss of kidney function requiring treatment of 472,000 patients with dialysis or transplantation in the US 1 . Diabetes and hypertension are the two leading reported causes of treated ESRD in the U.S. accounting for 44% and 27% of incident cases respectively 1 . African Americans have consistently had a much higher rate of ESRD than European Americans in the US. In 2005, African-Americans had a 3.7 times higher age adjusted risk of ESRD. The risk ratio by assigned primary cause of ESRD was 3.8 for hypertension, 2.6 for diabetes, 2.3 for glomerulonephritis, 2.1 for the other causes of kidney disease 1 . While lower socioeconomic status and poorer access to health care explains some of this excess risk 2-4 , African Americans appear to have greater risk than European Americans after these factors are taken into account. Family studies show clustering of ESRD independent of hypertension and diabetes 5, 6 with one large study shows stronger aggregation in African Americans 6 . Studies attempting to detect susceptibility genes for ESRD and other complex diseases are challenging due to the late age of onset, causing difficulty in collecting multiply-affected families, and because linkage analysis has suggested that there are no genes of high penetrance (>4-fold increased risk) in populations of European descent, the focus of most published studies 7, 8 . For these reasons, ESRD is an excellent phenotype for whole genome association analysis, an approach with enhanced power to detect common variants of modest penetrance, and with the further advantage that unrelated individuals can be studied.We performed a scan for ESRD genes using a particular type of whole genome association analysis, termed admixture mapping or mapping by admixture linkage disequilibrium (MALD) Linda NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 9-11 . Admixture mapping is particularly suitable for finding genetic risk alleles that differ in frequency between populations which we hypothesized might be the case for ESRD.The...