Focal Segmental Glomerulosclerosis 4, Susceptibility To

A number sign (#) is used with this entry because susceptibility to this form of renal disease, referred to here as focal segmental glomerulosclerosis-4 (FSGS4), is conferred by variation in the APOL1 gene (603743) on chromosome 22q12. These APOL1 variants confer protection against infection with T. b. rhodesiense, a human-specific Trypanosoma subspecies. Susceptibility to this form of FSGS is prevalent in populations of African ancestry.

Description

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).

Mapping

To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), Kopp et al. (2008) carried out an admixture mapping linkage disequilibrium genome scan in 190 African American individuals with FSGS and 222 controls. They identified a chromosome 22q12 region with a genomewide lod score of 9.2 and a peak lod of 12.4 centered on MYH9 (160775), a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly in haplotypes spanning exons 14 through 23 (odds ratio = 5.0, 95% confidence interval = 3.5-7.1; P = 4 x 10(-23), n = 852). Kopp et al. (2008) found that their association extended to hypertensive end-stage renal disease (ESRD) (odds ratio = 2.2, 95% confidence interval = 1.5-3.4; n = 433), but not type 2 diabetic ESRD (n = 476). Kopp et al. (2008) concluded that genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESRD among African Americans. For 3 MYH9 intron 23 SNPs in strong linkage disequilibrium (rs4821480, rs2032487, and rs4821481), 79 to 83% of the association was attributable to the SNPs alone, with the remaining fraction attributable to chromosomal ancestry. The single strongest risk allele within MYH9 was at rs2032487, which had a P value for idiopathic FSGS of 7 x 10(-12) and a P value for HIV-1-associated FSGS of 8 x 10(-8).

Kao et al. (2008) independently performed a genomewide admixture scan in 1,372 end-stage renal disease (ESRD) cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 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% confidence interval = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.02 to 0.06) in MYH9, the gene encoding nonmuscle myosin heavy chain type II isoform A, were associated with 2 to 4 times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans. This risk was associated with all nondiabetes ESRD with a lod score of 4.55 and also with hypertensive ESRD at 1.79, FSGS at 2.47, and HIV-related ESRD at 2.09. Kao et al. (2008) showed that any of the 3 SNPs, rs4821480, rs2032487, and rs4821481, in strong linkage disequilibrium is sufficient to account for all of the association between the excess African ancestry observed on chromosome 22q12 and nondiabetic ESRD.

Molecular Genetics

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).

Nomenclature

In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often been used to refer to the same disease entity. In OMIM, these disorders are designated as NPHS or FSGS according to how they were first described in the literature.