APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy

Abstract

Trypanolytic variants in APOL1, which encodes apolipoprotein L1, associate with kidney disease in African Americans, but whether APOL1-associated glomerular disease has a distinct clinical phenotype is unknown. Here we determined APOL1 genotypes for 271 African American cases, 168 European American cases, and 939 control subjects. In a recessive model, APOL1 variants conferred seventeenfold higher odds (95% CI 11 to 26) for focal segmental glomerulosclerosis (FSGS) and twenty-ninefold higher odds (95% CI 13 to 68) for HIV-associated nephropathy (HIVAN). FSGS associated with two APOL1 risk alleles associated with earlier age of onset (P ϭ 0.01) and faster progression to ESRD (P Ͻ 0.01) but similar sensitivity to steroids compared with other subjects. Individuals with two APOL1 risk alleles have an estimated 4% lifetime risk for developing FSGS, and untreated HIVinfected individuals have a 50% risk for developing HIVAN. The effect of carrying two APOL1 risk alleles explains 18% of FSGS and 35% of HIVAN; alternatively, eliminating this effect would reduce FSGS and HIVAN by 67%. A survey of world populations indicated that the APOL1 kidney risk alleles are present only on African chromosomes. In summary, African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly. These data add to the evidence base required to determine whether genetic testing for APOL1 has a use in clinical practice.

Defining cell-type specificity at the transcriptional level in human disease

“…The latter captures a different pool of transcripts: Abundantly expressed noncell-lineage-specific genes constitute the majority of the transcripts correlated with renal function, but these transcripts do not necessarily perform cell-lineage-specific functions and may not be associated with hereditary disease. For example, expression levels of MYO1E and APOL1 are not strongly correlated to GFR (ranked 1236 and 7430, respectively, by GFR-expression correlation), yet these two genes were identified by nanodissection to be cell-typespecific and have been shown experimentally (independent of and parallel to our work) to cause hereditary glomerular disease (Genovese et al 2010;Kopp et al 2011;Mele et al 2011) Furthermore, a systematic analysis focusing on literature-curated hereditary FSGS-associated genes that do not overlap with our podocyte gold standard (see Supplemental Methods) also demonstrates that a genome-wide assessment of GFR-transcript expression correlation alone could not identify genes associated with this hereditary renal disease (Supplemental Fig. 8A).…”

“…In addition to the de novo identified podocyte-specific genes, genes that have been shown by genetic or functional studies to be causally involved in hereditary glomerular diseases and chronic progressive renal failure, including DACH1 (nanodissection rank 184) (Köttgen et al 2010), APOL1 (rank 185) (Genovese et al 2010;Kopp et al 2011), VEGFA (rank 247) (Eremina et al 2008;Köttgen et al 2010), and MYH9 (rank 260) (Kao et al 2008;Kopp et al 2008), were ranked highly by our method. During the preparation of this manuscript, MYO1E (rank 75) was reported to be associated with autosomal-recessive, glucocorticoid-resistant nephrotic syndrome (Mele et al 2011).…”

Focal Segmental Glomerulosclerosis

“…A similar renal syndrome can be reproduced in transgenic mice bearing HIV-1 Nef (81) or Vpr (82) accessory proteins, suggesting possible mechanisms. Interestingly, the effect of HIV on podocytes is strongest in individuals with two APOL1 risk alleles, with an odds ratio of 29 in the United States (83) and an odds ratio of 89 in South Africa (84). Most individuals with HIV-associated nephropathy (HIVAN) have one or two APOL1 risk alleles.…”

“…One setting in which the adaptive processes drive APOL1 FSGS is perhaps the report that APOL1 variants are associated with proteinuric sickle cell nephropathy (97), although a systematic study of kidney histology in APOL1-associated sickle nephropathy is still lacking. APOL1 high-risk alleles are strongly associated with collapsing glomerulopathy in several settings: (1) HIVAN, in which 72% have two APOL1 high-risk alleles (83), and (2) the use of exogenous IFN (98) and in lupus (99).…”

Evolution of the primate trypanolytic factor APOL1

“…Two main coding variants associated with renal disease have been identified: the G1 allele, consisting of two amino acid substitutions (NM_003661.3 p.S342G and p.I384M) in near-perfect linkage, and the G2 allele, defined by a 2-aa deletion at the C terminus (NM_003661.3 p.delN388/Y389). Two copies of either of these renal risk variants (RRVs) cause a 7-to 10-fold increased risk of hypertensionassociated end-stage renal disease (1, 3), a 10-to 17-fold increase in focal and segmental glomerulosclerosis (a primary disease of the renal microvasculature) (1,4), and a 29-fold increase in HIV nephropathy (4). The high frequency of these RRVs in African Americans and the Yoruba (Nigeria) and their absence in Europeans and Asians suggest that positive selection increased the frequency of these APOL1 RRVs in Africa (1).…”