Linkage disequilibrium analysis reveals an albuminuria risk haplotype containing three missense mutations in the cubilin gene with striking differences among European and African ancestry populations

BMC Nephrol. 2012 Oct 31;13:142. doi: 10.1186/1471-2369-13-142.


Background: 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.

Methods: We implemented a Linkage Disequilibrium (LD) search with data from the 1000 Genomes Project, on African and European population genomic sequences.

Results: We 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.

Conclusions: Genotyping 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • African Continental Ancestry Group / genetics*
  • Albuminuria / diagnosis
  • Albuminuria / genetics*
  • Databases, Genetic
  • European Continental Ancestry Group / genetics*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genetic Variation / genetics
  • Haplotypes / genetics*
  • Humans
  • Linkage Disequilibrium / genetics*
  • Male
  • Mutation, Missense / genetics*
  • Pilot Projects
  • Receptors, Cell Surface / genetics*


  • Receptors, Cell Surface
  • intrinsic factor-cobalamin receptor