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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 disease1. 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 (Prec) = 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.

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Figure 1: Association P value plot of the GPC5 region in nephrotic syndrome and LD construction.
Figure 2: Association between rs16946160 genotype and GPC5 mRNA expression and localization of expression in human kidney.
Figure 3: In vitro functional analysis of GPC5.
Figure 4: PAN-FGF2–induced nephrotic syndrome in wild-type sibling (sib) mice is attenuated by Gpc5 conditional knockdown.
Figure 5: siRNA against Gpc5 ameliorates PAN-FGF2–induced nephrotic syndrome and Adriamycin-induced albuminuria.

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Acknowledgements

We thank all participating doctors and staff from collaborating institutes for providing DNA samples. We also thank the technical staff of the Laboratory for Endocrinology and Metabolism at the RIKEN Center for Genomic Medicine for providing technical assistance. This study was partially supported by the BioBank Japan Project on the Implementation of Personalized Medicine, Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, to E.N. (#3023168). This study was also supported by a Grant-in-Aid for Scientific research on Priority Area 'Comprehensive Genomics' from MEXT, Japan to K.T. (#17020003).

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Authors

Contributions

K.O. performed all experimental work and data analysis and wrote the first draft of the manuscript. A.T. and M.K. obtained raw GWAS data. N.N. supported the variation screening. Y.N. planned and designed the BioBank project. K.O., S.M., K.T. and E.N. designed the experiments. T.F., S.M., A.M., K.T. and E.N. supervised the project. K.D., H.S., T.K. and T.W. collected the case data and clinical data. The manuscript was finalized by K.O. with the assistance of all authors.

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Correspondence to Eisei Noiri.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–10. (PDF 1388 kb)

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Okamoto, K., Tokunaga, K., Doi, K. et al. Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet 43, 459–463 (2011). https://doi.org/10.1038/ng.792

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