Common variation in GPC5 is associated with acquired nephrotic syndrome

Koji Okamoto, Katsushi Tokunaga, Kent Doi, Toshiro Fujita, Hodaka Suzuki, Tetsuo Katoh, Tsuyoshi Watanabe, Nao Nishida, Akihiko Mabuchi, Atsushi Takahashi, Michiaki Kubo, Shiro Maeda, Yusuke Nakamura, Eisei Noiri

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)459-465
Number of pages7
JournalNature Genetics
Issue number5
Publication statusPublished - 05-2011

All Science Journal Classification (ASJC) codes

  • Genetics


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