title: Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.
abstract: MYH9 has been proposed as a major genetic risk locus for a spectrum of nondiabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African-specific missense mutations (S342G and I384M) in the neighboring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. The APOL1 gene product, apolipoprotein L-1, has been studied for its roles in trypanosomal lysis, autophagic cell death, lipid metabolism, as well as vascular and other biological activities. We also show that the distribution of these newly identified APOL1 risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to MYH9.Mapping by admixture linkage disequilibrium (MALD) localized an interval on chromosome 22, in a region that includes the MYH9 gene, which was shown to contain African ancestry risk variants associated with certain forms of ESKD (Kao et al. 2008; Kopp et al. 2008). MYH9 encodes nonmuscle myosin heavy chain IIa, a major cytoskeletal nanomotor protein expressed in many cell types, including podocyte cells of the renal glomerulus. Moreover, 39 different coding region mutations in MYH9 have been identified in patients with a group of rare syndromes, collectively termed the Giant Platelet Syndromes, with clear autosomal dominant inheritance, and various clinical manifestations, sometimes also including glomerular pathology and chronic kidney disease (Kopp 2010; Sekine et al. 2010). Accordingly, MYH9 was further explored in these studies as the leading candidate gene responsible for the MALD signal. Dense mapping of MYH9 identified individual single nucleotide polymorphisms (SNPs) and sets of such SNPs grouped as haplotypes that were found to be highly associated with a large and important group of ESKD risk phenotypes, which as a consequence were designated as MYH9-associated nephropathies (Bostrom and Freedman 2010). These included HIV-associated nephropathy (HIVAN), primary nonmonogenic forms of focal segmental glomerulosclerosis, and hypertension affiliated chronic kidney disease not attributed to other etiologies (Bostrom and Freedman 2010). The MYH9 SNP and haplotype associations observed with these forms of ESKD yielded the largest odds ratios (OR) reported to date for the association of common variants with common disease risk (Winkler et al. 2010). Two specific MYH9 variants (rs5750250 of S-haplotype and rs11912763 of F-haplotype) were designated as most strongly predictive on the basis of Receiver Operating Characteristic analysis (Nelson et al. 2010). These MYH9 association studies were then also extended to earlier stage and related kidney disease phenotypes and to population groups with varying degrees of recent African ancestry admixture (Behar et al. 2010; Freedman et al. 2009a, b; Nelson et al. 2010), and led to the expectation of finding a functional African ancestry causative variant within MYH9. However, despite intensive efforts including re-sequencing of the MYH9 gene no suggested functional mutation has been identified (Nelson et al. 2010; Winkler et al. 2010). This led us to re-examine the interval surrounding MYH9 and to the detection of novel missense mutations with predicted functional effects in the neighboring APOL1 gene, which are significantly more associated with ESKD than all previously reported SNPs in MYH9.
authors.affiliation: Ruth and Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Shay
authors.initials: S
authors.lastname: Tzur
authors.forename: Saharon
authors.initials: S
authors.lastname: Rosset
authors.forename: Revital
authors.initials: R
authors.lastname: Shemer
authors.forename: Guennady
authors.initials: G
authors.lastname: Yudkovsky
authors.forename: Sara
authors.initials: S
authors.lastname: Selig
authors.forename: Ayele
authors.initials: A
authors.lastname: Tarekegn
authors.forename: Endashaw
authors.initials: E
authors.lastname: Bekele
authors.forename: Neil
authors.initials: N
authors.lastname: Bradman
authors.forename: Walter G
authors.initials: WG
authors.lastname: Wasser
authors.forename: Doron M
authors.initials: DM
authors.lastname: Behar
authors.forename: Karl
authors.initials: K
authors.lastname: Skorecki
mesh_terms: D000349:Africa; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics*; D015810:Linkage Disequilibrium; D008075:Lipoproteins, HDL / Q000235:genetics*; D020409:Molecular Motor Proteins / Q000235:genetics*; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
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