Common variation in GPC5 is associated with acquired nephrotic syndrome

Nat Genet. 2011 May;43(5):459-63. doi: 10.1038/ng.792. Epub 2011 Mar 27.


Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P(rec)) = 6.0 × 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Base Sequence
  • Case-Control Studies
  • DNA Primers / genetics
  • Disease Models, Animal
  • Female
  • Gene Knockdown Techniques
  • Genome-Wide Association Study
  • Glypicans / antagonists & inhibitors
  • Glypicans / deficiency
  • Glypicans / genetics*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Models, Genetic
  • Nephrotic Syndrome / genetics*
  • Nephrotic Syndrome / metabolism
  • Nephrotic Syndrome / pathology
  • Podocytes / metabolism
  • Polymorphism, Single Nucleotide
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics


  • DNA Primers
  • GPC5 protein, human
  • Glypicans
  • Gpc5 protein, mouse
  • RNA, Messenger
  • RNA, Small Interfering