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The p.R229Q variant of the NPHS2 (podocin) gene in focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome: a meta-analysis

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Abstract

While many previous studies have reported an association between the p.R229Q variant of the NPHS2 gene and focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS), a conclusive relationship has not been defined. In this study, we performed a meta-analysis of the published data to investigate the impact of the p.R229Q polymorphism on FSGS and SRNS patients. Despite significant heterogeneity within some of the comparisons, the results revealed significantly higher risks of SRNS in individuals homozygous for the variant allele (OR 7.411, 95 % confidence interval 1.876–29.436, p = 0.004) compared to homozygous non-variant individuals. However, the carrier rate of the p.R229Q variant was not significantly different between SRNS patients and steroid-sensitive nephrotic syndrome patients. No statistically significant differences in the p.R229Q carrier rate were observed between FSGS patients and controls or FSGS patients and patients with different pathology classifications. No notable differences in the p.R229Q carrier rate were found between patients and controls in any group with early-onset disease (onset age < 18). In conclusion, our meta-analysis suggests that for adult-onset disease (onset age > 18), the homozygous variant could be a potential predictor of hereditary nephrotic syndrome and that the p.R229Q allele cannot currently be considered a risk factor for predicting FSGS.

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References

  1. McKinney PA, Feltbower RG, Brocklebank JT et al (2001) Time trends and ethnic patterns of childhood nephrotic syndrome in Yorkshire. UK. Pediatr Nephrol 16(12):1040–1044

    Article  CAS  Google Scholar 

  2. Voskarides K, Arsali M, Athanasiou Y et al (2012) Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria. Pediatr Nephrol 27(4):675–679

    Article  PubMed  Google Scholar 

  3. Iseki K, Tokashiki K, Iseki C et al (2008) Proteinuria and decreased body mass index as a significant risk factor in developing end-stage renal disease. Clin Exp Nephrol 12(5):363–369

    Article  PubMed  Google Scholar 

  4. Mekahli D, Liutkus A, Ranchin B et al (2009) Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study. Pediatr Nephrol 24(8):1525–1532

    Article  PubMed  Google Scholar 

  5. Sgambat K, Banks M, Moudgil A. Effect of galactose on glomerular permeability and proteinuria in steroid-resistant nephrotic syndrome. Pediatr Nephrol 2013

  6. Chun MJ, Korbet SM, Schwartz MM et al (2004) Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. J Am Soc Nephrol 15(8):2169–2177

    Article  PubMed  Google Scholar 

  7. Wei C, Trachtman H, Li J et al (2012) Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 23(12):2051–2059

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Buscher AK, Kranz B, Buscher R et al (2010) Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5(11):2075–2084

    Article  PubMed Central  PubMed  Google Scholar 

  9. Khurana S, Chakraborty S, Lam M et al (2012) Familial focal segmental glomerulosclerosis (FSGS)-linked alpha-actinin 4 (ACTN4) protein mutants lose ability to activate transcription by nuclear hormone receptors. J Biol Chem 287(15):12027–12035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Mukerji N, Damodaran TV, Winn MP (2007) TRPC6 and FSGS: the latest TRP channelopathy. Biochim Biophys Acta 1772(8):859–868

    Article  CAS  PubMed  Google Scholar 

  11. Gigante M, Pontrelli P, Montemurno E et al (2009) CD2AP mutations are associated with sporadic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS). Nephrol Dial Transplant 24(6):1858–1864

    Article  CAS  PubMed  Google Scholar 

  12. Pei Y (2011) INF2 is another piece of the jigsaw puzzle for FSGS. J Am Soc Nephrol 22(2):197–199

    Article  PubMed  Google Scholar 

  13. steroidsAnochie IC, Eke FU, Okpere AN. Familial Focal Segmental Glomerulosclerosis (FSGS) in a Nigerian Family and Exclusion of Mutations in NPHS2,WT1 and APOL1. West Afr J Med 2012;31(4):273-276

    Google Scholar 

  14. Boute N, Gribouval O, Roselli S et al (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24(4):349–354

    Article  CAS  PubMed  Google Scholar 

  15. Tsukaguchi H, Sudhakar A, Le TC et al (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest 110(11):1659–1666

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Zhang SY, Marlier A, Gribouval O et al (2004) In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation. Kidney Int 66(3):945–954

    Article  CAS  PubMed  Google Scholar 

  17. Karle SM, Uetz B, Ronner V et al (2002) Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13(2):388–393

    CAS  PubMed  Google Scholar 

  18. Machuca E, Hummel A, Nevo F et al (2009) Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. Kidney Int 75(7):727–735

    Article  CAS  PubMed  Google Scholar 

  19. Santin S, Bullich G, Tazon-Vega B et al (2011) Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6(5):1139–1148

    Article  PubMed Central  PubMed  Google Scholar 

  20. Reiterova J, Safrankova H, Obeidova L et al (2012) Mutational analysis of the NPHS2 gene in Czech patients with idiopathic nephrotic syndrome. Folia Biol (Praha) 58(2):64–68

    CAS  Google Scholar 

  21. McKenzie LM, Hendrickson SL, Briggs WA et al (2007) NPHS2 variation in sporadic focal segmental glomerulosclerosis. J Am Soc Nephrol 18(11):2987–2995

    Article  CAS  PubMed  Google Scholar 

  22. Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F et al (2006) Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods 11(2):193–206

    Article  PubMed  Google Scholar 

  23. Yu Z, Ding J, Huang J et al (2005) Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children. Nephrol Dial Transplant 20(5):902–908

    Article  CAS  PubMed  Google Scholar 

  24. Xia Y, Mao J, Jin X, et al. Familial steroid-sensitive idiopathic nephrotic syndrome: seven cases from three families in China. Clinics (Sao Paulo) 2013;68(5)

  25. Maruyama K, Iijima K, Ikeda M et al (2003) NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children. Pediatr Nephrol 18(5):412–416

    PubMed  Google Scholar 

  26. Mao J, Zhang Y, Du L et al (2007) NPHS1 and NPHS2 gene mutations in Chinese children with sporadic nephrotic syndrome. Pediatr Res 61(1):117–122

    Article  CAS  PubMed  Google Scholar 

  27. Cho HY, Lee JH, Choi HJ et al (2008) WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23(1):63–70

    Article  PubMed  Google Scholar 

  28. Lipska BS, Iatropoulos P, Maranta R et al (2013) Genetic screening in adolescents with steroid-resistant nephrotic syndrome. Kidney Int 84(1):206–213

    Article  CAS  PubMed  Google Scholar 

  29. Chernin G, Heeringa SF, Vega-Warner V et al (2010) Adequate use of allele frequencies in Hispanics–a problem elucidated in nephrotic syndrome. Pediatr Nephrol 25(2):261–266

    Article  PubMed Central  PubMed  Google Scholar 

  30. Buscher AK, Konrad M, Nagel M et al (2012) Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. Clin Nephrol 78(1):47–53

    Article  PubMed  Google Scholar 

  31. Taylor A, Kim-Cohen J (2007) Meta-analysis of gene-environment interactions in developmental psychopathology. Dev Psychopathol 19(4):1029–1037

    Article  PubMed  Google Scholar 

  32. Franceschini N, North KE, Kopp JB et al (2006) NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review. Genet Med 8(2):63–75

    Article  CAS  PubMed  Google Scholar 

  33. Koziell A, Grech V, Hussain S et al (2002) Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 11(4):379–388

    Article  CAS  PubMed  Google Scholar 

  34. Santin S, Tazon-Vega B, Silva I et al (2011) Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6(2):344–354

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Kerti A, Csohany R, Wagner L et al (2013) NPHS2 homozygous p. R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis. Pediatr Nephrol 28(10):2061–2064

    Article  PubMed  Google Scholar 

  36. Kottgen A, Hsu CC, Coresh J et al (2008) The association of podocin R229Q polymorphism with increased albuminuria or reduced estimated GFR in a large population-based sample of US adults. Am J Kidney Dis 52(5):868–875

    Article  PubMed Central  PubMed  Google Scholar 

  37. He N, Zahirieh A, Mei Y et al (2007) Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2(1):31–37

    Article  CAS  PubMed  Google Scholar 

  38. Tonna SJ, Needham A, Polu K et al (2008) NPHS2 variation in focal and segmental glomerulosclerosis. BMC Nephrol 9:13

    Article  PubMed Central  PubMed  Google Scholar 

  39. Aucella F, De Bonis P, Gatta G et al (2005) Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis. Nephron Clin Pract 99(2):c31–c36

    Article  CAS  PubMed  Google Scholar 

  40. Gbadegesin R, Hinkes B, Vlangos C et al (2007) Mutational analysis of NPHS2 and WT1 in frequently relapsing and steroid-dependent nephrotic syndrome. Pediatr Nephrol 22(4):509–513

    Article  PubMed  Google Scholar 

  41. Abid A, Khaliq S, Shahid S et al (2012) A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan. Gene 502(2):133–137

    Article  CAS  PubMed  Google Scholar 

  42. Berdeli A, Mir S, Yavascan O et al (2007) NPHS2 (podicin) mutations in Turkish children with idiopathic nephrotic syndrome. Pediatr Nephrol 22(12):2031–2040

    Article  PubMed  Google Scholar 

  43. Caridi G, Bertelli R, Di Duca M et al (2003) Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol 14(5):1278–1286

    Article  CAS  PubMed  Google Scholar 

  44. Weber S, Gribouval O, Esquivel EL et al (2004) NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 66(2):571–579

    Article  CAS  PubMed  Google Scholar 

  45. Ruf RG, Lichtenberger A, Karle SM et al (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15(3):722–732

    Article  PubMed  Google Scholar 

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Acknowledgments

This research is supported by the National Science Foundation of China (No. 81173457).

Conflict of interest

We declare that we have no financial or personal relationships with other people or organisations that can inappropriately influence our work; there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, this manuscript.

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Authors and Affiliations

  1. Department of Traditional Chinese Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Lu Lu, Yi Yin, Ming Wang, Dong-Tao Wang, Yin Shi & Lian-Bo Wei

  2. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China

    Lu Lu, Yi Yin, Yu-Cong Zou, Dong-Tao Wang, Yin Shi & Lian-Bo Wei

  3. Department of Endocrinology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510280, China

    Heng Wan

  4. Department of Orthopaedics, The First Affiliated Hospital, Guangzhou University of TCM, Guangzhou, 510405, China

    Wen-Jun Feng

  5. Department of Nephrology, ZhuJiang Hospital, Southern Medical University, Guangzhou, 510280, China

    Bo Huang & Yan Zhao

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  1. Lu Lu
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  2. Heng Wan
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Correspondence to Lian-Bo Wei.

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Lu Lu, Heng Wan and Yi Yin have contributed equally to this article.

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Lu, L., Wan, H., Yin, Y. et al. The p.R229Q variant of the NPHS2 (podocin) gene in focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome: a meta-analysis. Int Urol Nephrol 46, 1383–1393 (2014). https://doi.org/10.1007/s11255-014-0676-3

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  • DOI: https://doi.org/10.1007/s11255-014-0676-3

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