Focal segmental glomerulosclerosis (FSGS) is a pathologic entity associated clinically with proteinuria, the nephrotic syndrome (NPHS), and progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD) (Meyrier, 2005).
For a ... Focal segmental glomerulosclerosis (FSGS) is a pathologic entity associated clinically with proteinuria, the nephrotic syndrome (NPHS), and progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD) (Meyrier, 2005). For a general phenotypic description and a discussion of genetic heterogeneity of focal segmental glomerulosclerosis and nephrotic syndrome, see FSGS1 (603278).
Although genetic variation in or near the MYH9 gene on chromosome 22 was associated with increased risk of FSGS, causal mutations in MHY9 had not been identified. Genomewide analyses showed a strong signal of natural selection in the ... Although genetic variation in or near the MYH9 gene on chromosome 22 was associated with increased risk of FSGS, causal mutations in MHY9 had not been identified. Genomewide analyses showed a strong signal of natural selection in the region containing the MHY9 and APOL1 (603743) genes. The longer patterns of linkage disequilibrium (LD) associated with variants undergoing natural selection suggested to Genovese et al. (2010) that a positively selected risk variant could be in a larger interval containing the APOL genes rather than be confined to MYH9. In an association analysis comparing 205 African Americans with biopsy-proven FSGS and no family history of FSGS with 180 African American controls, Genovese et al. (2010) identified association of kidney disease with 2 independent sequence variants in the last exon of the APOL1 gene (FSGS odds ratio = 10.5, 95% confidence interval 6.0 to 18.4; ESRD odds ratio = 7.3, 95% confidence interval 5.6 to 9.5). Association with renal disease was confirmed in a larger cohort of 1,030 African American cases with ESRD and 1,025 geographically matched African American controls. The 2 APOL1 variants, which Genovese et al. (2010) referred to as G1 (603743.0001) and G2 (603743.0002), are common in African chromosomes but absent in European chromosomes, and both reside within haplotypes that harbor signatures of positive selection. APOL1 is a serum factor that lyses trypanosomes. In vitro assays revealed that only the kidney disease-associated APOL1 variants lysed Trypanosoma brucei rhodesiense. Association of renal disease with MYH9 sequence variants disappeared after controlling for the APOL1 risk variants. Comparing participants with zero or 1 risk allele of APOL1 to participants with 2 risk alleles provided an odds ratio for FSGS of 10.5 (confidence interval 6.0 to 18.4). This analysis supported a completely recessive pattern of inheritance. Genovese et al. (2010) speculated that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans. Parsa et al. (2013) performed 2 studies examining the effects of variants in the APOL1 gene on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), 693 black patients with chronic kidney disease attributed to hypertension were examined for a primary outcome of composite end-stage renal disease or doubling of the serum creatinine level. A total of 160 (23%) individuals carried 2 copies of APOL1 risk variants G1 (603743.0001) and/or G2 (603743.0002). Of these individuals in the high-risk group, the primary outcome occurred in 58%; in the APOL1 low-risk group (all other genotypes), the primary outcome occurred in 37% (hazard ratio in the high-risk group, 1.88; p less than 0.001). In the Chronic Renal Insufficiency Cohort (CRIC), Parsa et al. (2013) evaluated 2,955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) for the primary outcomes of the slope of the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease, or a reduction of 50% in the eGFR from baseline. Black patients were genotyped for the G1 and G2 risk alleles. In the CRIC study, black patients in the APOL1 high-risk group (270 of 1,411 total black patients) had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, with or without diabetes as a complication (p less than 0.001 for all comparisons).