MYH9 and APOL1 are both associated with sickle cell disease nephropathy

Abstract

SUMMARY Background Renal failure occurs in 5–18% of sickle cell disease (SCD) patients and is associated with early mortality. At risk SCD patients cannot be identified prior to the appearance of proteinuria and the pathobiology is not well understood. The MYH9 and APOL1 genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans. Methods We genotyped 26 SNPs in MYH9 and 2 SNPs in APOL1 in 521 unrelated adult (18–83 years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria. Results Eight MYH9 SNPs and one APOL1 SNP were nominally associated with proteinuria. Six SNPs remained significant after multiple testing correction (p < 0.0025), and a risk haplotype was associated with proteinuria (p=0.001). Using multiple regression, association with APOL1 diminished in the presence of MYH9 SNPs. Glomerular filtration rate was negatively correlated with proteinuria (p < 0.0001), and was nominally associated with MYH9 and APOL1 in age-adjusted analyses. Conclusion Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 is more strongly associated than APOL1. These data also provide the opportunity for early identification of patients at risk and new therapeutics.

Focal Segmental Glomerulosclerosis

“…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).…”

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

“…16 The second found that individuals with the APOL1 G1/G2 risk variants (defined as being homozygous or compound heterozygous for the G1 and/or G2 risk variants using a recessive model) were 3.4-times more likely to have dipstick-defined proteinuria and that variants in MYH9 were independently associated with proteinuria after adjusting for APOL1 variant status. 17 Furthermore, a significant interaction between the APOL1 G1/G2 risk variants and an MYH9 risk haplotype was observed in predicting eGFR.…”

“…Variants in BMPR1B (rs2240036, rs4145993, rs17022863, rs1434549, rs1470409, rs4331783) and MYH9 (rs5756129, rs11912763, rs16996648, rs5750248, rs1557529, rs5756152, rs8141189, rs1005570. rs16996672, rs933224) that had been previously identified in the literature as being associated with sickle cell nephropathy 16,17 were also examined for associations with eGFR and urine albumin concentrations, respectively. The imputation qualities for BMPRIB and MYH9 are provided in Online Supplementary Table S1. HMOX1 and SOD2 were candidate genes identified as having differential expression from the PCR experiments.…”

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

“…This scenario is proposed for renal disease associated with sickle cell disease, with collapsing nephropathy associated with lupus or HIV and with compromised graft survival after transplantation. [4][5][6][7][8][9] APOL1 risk variants are associated with earlier age of onset and progression to renal failure of subjects with FSGS, and prospective studies in the African American Study of Kidney Disease and Chronic Renal Insufficiency cohorts show that carriage of two APOL1 risk variants is associated with more rapid progression to clinical endpoints in persons with renal insufficiency at study entry. 2,3,5,7,8 Moreover, African-American participants without renal disease on enrolment in the ARIC study were more likely to develop CKD and to progress to renal failure if they had two APOL1 risk alleles, compared with those with no alleles or one allele.…”