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Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy
Santosh L Saraf1, Xu Zhang2, Binal Shah2
1Division of Hematology & Oncology, Department of Medicine, Comprehensive Sickle Cell Center, University of Illinois at Chicago, IL ssaraf@uic.edu vgordeuk@uic.edu.
Haematologica
|July 25, 2015
Summary
Genetic variants in APOL1 G1/G2 are linked to kidney disease in sickle cell disease patients, potentially by increasing hemoglobinuria risk. HMOX1 variants also associate with kidney disease, possibly by reducing protection against hemoglobin toxicity.
Area of Science:
- Nephrology
- Genetics
- Hematology
Background:
- Sickle cell nephropathy is linked to intravascular hemolysis and hemoglobinuria.
- APOL1 G1/G2 variants are strong genetic predictors of kidney disease in African-Americans.
- APOL1's role in cell-free hemoglobin scavenging is mediated by haptoglobin-related protein.
Purpose of the Study:
- To investigate the association of APOL1 G1/G2 and HMOX1 variants with kidney disease in sickle cell disease (SCD).
- To explore the relationship between cell-free hemoglobin, kidney injury markers, and genetic factors in SCD patients.
Main Methods:
- Replicated association of APOL1 G1/G2 with proteinuria and hemoglobinuria in SCD patients from two cohorts.
- Assessed correlation between urine kidney injury molecule-1 and cell-free hemoglobin in vitro and in SCD patients.
- Investigated association of HMOX1 variants (rs743811, GT-tandem repeats) with chronic kidney disease (CKD) and end-stage renal disease (ESRD) in SCD cohorts.
Main Results:
- APOL1 G1/G2 strongly associated with hemoglobinuria (OR=2.5-2.6) and proteinuria in SCD.
- Urine kidney injury molecule-1 correlated with cell-free hemoglobin; in vitro exposure induced kidney injury markers and reduced cell viability.
- HMOX1 rs743811 associated with CKD (OR=3.0) and ESRD (OR=10.0); longer HMOX1 GT-tandem repeats linked to lower eGFR.
Conclusions:
- APOL1 G1/G2 variants are associated with kidney disease in SCD, likely via increased risk of hemoglobinuria.
- HMOX1 variants are associated with kidney disease in SCD, potentially due to impaired protection against hemoglobin-induced kidney toxicity.
- Findings highlight genetic contributions to nephropathy in sickle cell disease.
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