Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene

摘要: MYH9 has been proposed as a major genetic risk locus for 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 neighboring APOL1 gene, demonstrate that these are more strongly associated with ESKD than previously reported variants. The gene product, apolipoprotein L-1, studied its roles trypanosomal lysis, autophagic cell death, lipid metabolism, well vascular other biological activities. also show distribution newly identified variants African populations is consistent pattern ancestry attributed MYH9.Mapping by admixture linkage disequilibrium (MALD) localized an interval on chromosome 22, region includes which was shown contain certain forms (Kao et al. 2008; Kopp 2008). encodes nonmuscle myosin heavy chain IIa, cytoskeletal nanomotor protein expressed many types, including podocyte cells renal glomerulus. Moreover, 39 different coding have patients group rare syndromes, collectively termed Giant Platelet Syndromes, clear autosomal dominant inheritance, various clinical manifestations, sometimes glomerular pathology chronic (Kopp 2010; Sekine 2010). Accordingly, further explored studies leading candidate responsible MALD signal. Dense mapping individual single nucleotide polymorphisms (SNPs) sets such SNPs grouped haplotypes were found be highly large important phenotypes, consequence designated MYH9-associated nephropathies (Bostrom Freedman These included HIV-associated nephropathy (HIVAN), primary nonmonogenic focal segmental glomerulosclerosis, hypertension affiliated not etiologies SNP haplotype associations observed yielded largest odds ratios (OR) date association common (Winkler Two specific (rs5750250 S-haplotype rs11912763 F-haplotype) most predictive basis Receiver Operating Characteristic analysis (Nelson then extended earlier related phenotypes population groups varying degrees recent (Behar 2009a, b; Nelson 2010), led expectation finding functional causative variant within MYH9. However, despite intensive efforts re-sequencing no suggested mutation Winkler This us re-examine surrounding detection novel predicted effects significantly all