Abstract
BackgroundA recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics.MethodsWe implemented a Linkage Disequilibrium (LD) search with data from the 1000 Genomes Project, on African and European population genomic sequences.ResultsWe found that the p.Ile2984Val variation is part of a larger haplotype in European populations and it is almost absent in west Africans. This haplotype contains 19 single nucleotide polymorphisms (SNPs) in very high LD, three of which are missense mutations (p.Leu2153Phe, p.Ile2984Val, p.Glu3002Gly), and two have not been previously reported. Notably, this European haplotype is absent in west African populations, and the frequency of each individual polymorphism differs significantly in Africans.ConclusionsGenotyping of these variants in existing African origin sample sets coupled to measurements of urine albumin excretion levels should reveal which is the most likely functional candidate for albuminuria risk. The unique haplotypic structure of CUBN in different populations may leverage the effort to identify the functional variant and to shed light on evolution of the CUBN gene locus.
Highlights
A recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics
In order to identify SNPs in the CUBN region that are in high Linkage Disequilibrium (LD) with the SNP reported by Boger et al we utilized the 1000 Genomes Project pilot dataset [14] containing the complete genome sequences of Africans from Yoruba (YRI), and individuals of European ancestry from Utah (CEU)
Of the 3,862 known SNPs in the 306 Kbp of the CUBN gene region, we have identified 18 SNPs that are in very high LD with the reported albuminuria associated variant in Europeans (Table 1)
Summary
A recent meta-analysis described a variant (p.Ile2984Val) in the cubilin gene (CUBN) that is associated with levels of albuminuria in the general population and in diabetics. A variant in the cubilin gene (CUBN) that is associated with albuminuria has been recently reported by Boger et al [8]. This gene encodes the cubilin receptor, which is a peripheral membrane protein expressed in the renal proximal tubule [9,10]. It is part of the megalin-cubilin complex receptor, responsible for the reabsorption of albumin [6] and other proteins present in the glomerular ultrafiltrate, minimizing their excretion in healthy human urine [6,10,11]. Rare mutations in the CUBN gene can cause hereditary megaloblastic anemia and proteinuria (Imerslund-Grasbeck syndrome) [12]
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