title: Common variation in GPC5 is associated with acquired nephrotic syndrome.
abstract: 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.
authors: Department of Nephrology and Endocrinology, University Hospital, The University of Tokyo, Tokyo, Japan.
authors: Koji
authors: K
authors: Okamoto
authors: Katsushi
authors: K
authors: Tokunaga
authors: Kent
authors: K
authors: Doi
authors: Toshiro
authors: T
authors: Fujita
authors: Hodaka
authors: H
authors: Suzuki
authors: Tetsuo
authors: T
authors: Katoh
authors: Tsuyoshi
authors: T
authors: Watanabe
authors: Nao
authors: N
authors: Nishida
authors: Akihiko
authors: A
authors: Mabuchi
authors: Atsushi
authors: A
authors: Takahashi
authors: Michiaki
authors: M
authors: Kubo
authors: Shiro
authors: S
authors: Maeda
authors: Yusuke
authors: Y
authors: Nakamura
authors: Eisei
authors: E
authors: Noiri
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D053673:Glypicans / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008957:Models, Genetic; D009404:Nephrotic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D017931:DNA Primers; C106228:GPC5 protein, human; D053673:Glypicans; C501209:Gpc5 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering