MYH9 and APOL1 are both associated with sickle cell disease nephropathy

• Type of Material: Article
• Authors: Allison E. Ashley-Koch, Duke University; Emmanuel C. Okocha, Duke University; Melanie E. Garrett, Duke University; Karen Soldano, Duke University; Laura M. De Castro, Duke University; Jude C. Jonassaint, Duke University; Eugene P. Orringer, University of North Carolina; James Eckman, Emory University; Marilyn J. Telen, Duke University
• Language: English
• Date: 2011-11-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Blackwell Publishing Ltd.
• Final Published Version (URL): http://dx.doi.org/10.1111/j.1365-2141.2011.08832.x
• Title of Journal or Parent Work: British Journal of Haematology
• ISSN: 0007-1048
• Volume: 155
• Issue: 3
• Start Page: 386
• End Page: 394
• Grant/Funding Information: This work was funded in part by RO1 HL079915 from the National Heart, Lung and Blood Institute, USA.; ECO received support from R90/T90 HG004150.
• Keywords: AFRICAN-AMERICANS; nephropathy; RISK; Life Sciences & Biomedicine; PREVALENCE; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; proteinuria; Science & Technology; sickle cell disease; PODOCYTES; genetics association; ANGIOTENSIN-CONVERTING ENZYME; ANEMIA; genetic modifier; KIDNEY-DISEASE; Hematology; LINKAGE PHASE; STAGE RENAL-DISEASE
• Research Categories: Biology, Genetics; Health Sciences, Oncology

Abstract

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 myosin, heavy chain 9, non-muscle (MYH9) and apolipoprotein L1 (APOL1) genes have been associated with risk for focal segmental glomerulosclerosis and end-stage renal disease in African Americans. We genotyped 26 single nucleotide polymorphisms (SNPs) in MYH9 and 2 SNPs in APOL1 (representing the G1 and G2 tags) in 521 unrelated adult (18-83years) SCD patients screened for proteinuria. Using logistic regression, SNPs were evaluated for association with proteinuria. Seven SNPs in MYH9 and one in APOL1 remained significantly associated with proteinuria after multiple testing correction (P<0·0025). An MYH9 risk haplotype (P=0·001) and the APOL1G1/G2 recessive model (P<0·0001) were strongly associated with proteinuria, even when accounting for the other. Glomerular filtration rate was negatively correlated with proteinuria (P<0·0001), and was significantly predicted by an interaction between MYH9 and APOL1 in age-adjusted analyses. Our data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 and APOL1 are both associated with risk.