title: MYH9 and APOL1 are both associated with sickle cell disease nephropathy.
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 (18-83 years) 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 APOL1 G1/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.
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. allison.ashleykoch@ duke.edu
authors.forename: Allison E
authors.initials: AE
authors.lastname: Ashley-Koch
authors.forename: Emmanuel C
authors.initials: EC
authors.lastname: Okocha
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Garrett
authors.forename: Karen
authors.initials: K
authors.lastname: Soldano
authors.forename: Laura M
authors.initials: LM
authors.lastname: De Castro
authors.forename: Jude C
authors.initials: JC
authors.lastname: Jonassaint
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Orringer
authors.forename: James R
authors.initials: JR
authors.lastname: Eckman
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Telen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics*; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007674:Kidney Diseases / Q000097:blood* / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains