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RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up

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Abstract

Aims

We investigated the association of polymorphisms of three genes implicated in oxidative stress: CYBA C242T, RAGE −374T/A and −429T/C, and ALOX12 Arg261Gln, with the delay of microalbuminuria onset in patients with type 1 diabetes mellitus (DT1).

Methods

A total of 162 T1D patients presenting with diabetes for 32.9 ± 9 years were included in the study; 53 had persistent microalbuminuria (>30 mg/l) and 109 did not. Onset of diabetes, microalbuminuria and end-stage renal disease (ESRD) were recorded as bio-clinical data. We determined polymorphism association of microalbuminuria with a Cox regression model.

Results

All polymorphisms respected the Hardy–Weinberg equilibrium. The Cox regression model validated four significant variables associated with microalbuminuria: RAGE 374AA (HR 4.19 [1.84–9.58] (p = 0.001)), CYBA TT+TC (HR 2.1 [1.16–3.80], p = 0.015), male sex (HR 1.92 [1.07–3.43], p = 0.028) and diabetes diagnosis at the pediatric stage (HR 1.85 [1.03–3.32], p = 0.039). The same association was found with ESRD (p = 0.028 and p = 0.033 for CYBA TC+TT and RAGE 374AA, respectively). CYBA C242T and RAGE 374T/A were not significantly associated with diabetic retinopathy.

Conclusions

CYBA C242T and RAGE −374T/A correlate with microalbuminuria onset in the French DT1 cohort. The same correlation with ESRD onset supports the argument for the involvement of a genetic predisposition involving kidney-specific oxidative stress for diabetic nephropathy.

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References

  1. Rosolowsky ET, Skupien J, Smiles AM et al (2011) Risk for ESRD in Type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol 22:545–553. doi:10.1681/ASN.2010040354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ritz E, Rychlík I, Locatelli F, Halimi S (1999) End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis Off J Natl Kidney Found 34:795–808. doi:10.1016/S0272-6386(99)70035-1

    Article  CAS  Google Scholar 

  3. D’Addio F, Trevisani A, Ben Nasr M et al (2014) Harnessing the immunological properties of stem cells as a therapeutic option for diabetic nephropathy. Acta Diabetol 51:897–904. doi:10.1007/s00592-014-0603-1

    Article  PubMed  Google Scholar 

  4. Doria A, Niewczas MA, Fiorina P (2012) Can existing drugs approved for other indications retard renal function decline in patients with type 1 diabetes and nephropathy? Semin Nephrol 32:437–444. doi:10.1016/j.semnephrol.2012.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820. doi:10.1038/414813a

    Article  CAS  PubMed  Google Scholar 

  6. Thallas-Bonke V, Thorpe SR, Coughlan MT et al (2008) Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway. Diabetes 57:460–469. doi:10.2337/db07-1119

    Article  CAS  PubMed  Google Scholar 

  7. Ha H, Hwang I-A, Park JH, Lee HB (2008) Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract 82(Suppl 1):S42–S45. doi:10.1016/j.diabres.2008.09.017

    Article  CAS  PubMed  Google Scholar 

  8. Bedard K, Krause K-H (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313. doi:10.1152/physrev.00044.2005

    Article  CAS  PubMed  Google Scholar 

  9. Babelova A, Avaniadi D, Jung O et al (2012) Role of Nox4 in murine models of kidney disease. Free Radic Biol Med 53:842–853. doi:10.1016/j.freeradbiomed.2012.06.027

    Article  CAS  PubMed  Google Scholar 

  10. Hodgkinson AD, Millward BA, Demaine AG (2003) Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with type 1 diabetes. Diabetes Care 26:3111–3115

    Article  CAS  PubMed  Google Scholar 

  11. Fang S, Wang L, Jia C (2010) Association of p22phox gene C242T polymorphism with coronary artery disease: a meta-analysis. Thromb Res 125:e197–e201. doi:10.1016/j.thromres.2010.01.001

    Article  CAS  PubMed  Google Scholar 

  12. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S (2012) Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury. Pharmacol Res Off J Ital Pharmacol Soc 65:297–302. doi:10.1016/j.phrs.2011.11.001

    CAS  Google Scholar 

  13. Wendt TM, Tanji N, Guo J et al (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:1123–1137. doi:10.1016/S0002-9440(10)63909-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Franko B, Brault J, Jouve T et al (2014) Differential impact of glucose levels and advanced glycation end-products on tubular cell viability and pro-inflammatory/profibrotic functions. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2014.08.042

    PubMed  Google Scholar 

  15. Hudson BI, Stickland MH, Futers TS, Grant PJ (2001) Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. Diabetes 50:1505–1511

    Article  CAS  PubMed  Google Scholar 

  16. Matsunaga-Irie S, Maruyama T, Yamamoto Y et al (2004) Relation between development of nephropathy and the p22phox C242T and receptor for advanced glycation end product G1704T gene polymorphisms in type 2 diabetic patients. Diabetes Care 27:303–307

    Article  CAS  PubMed  Google Scholar 

  17. Santos KG, Canani LH, Gross JL et al (2005) Relationship of p22phox C242T polymorphism with nephropathy in type 2 diabetic patients. J Nephrol 18:733–738

    CAS  PubMed  Google Scholar 

  18. Gu L, Su L, Liang B et al (2013) Association between the C242T polymorphism of p22phox gene and ischemic stroke: a meta-analysis. J Neurol Sci 330:100–110. doi:10.1016/j.jns.2013.04.022

    Article  CAS  PubMed  Google Scholar 

  19. Lim SC, Goh SK, Lai YR et al (2006) Relationship between common functional polymorphisms of the p22phox gene (−930A>G and +242C>T) and nephropathy as a result of Type 2 diabetes in a Chinese population. Diabet Med J Br Diabet Assoc 23:1037–1041. doi:10.1111/j.1464-5491.2006.01916.x

    Article  CAS  Google Scholar 

  20. Li A, Prasad A, Mincemoyer R et al (1999) Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function. Am J Med Genet 86:57–61. doi:10.1002/(SICI)1096-8628(19990903)86:1<57:AID-AJMG11>3.0.CO;2-R

    Article  CAS  PubMed  Google Scholar 

  21. Liu Y, Freedman BI, Burdon KP et al (2008) Association of arachidonate 12-lipoxygenase genotype variation and glycemic control with albuminuria in type 2 diabetes. Am J Kidney Dis Off J Natl Kidney Found 52:242–250. doi:10.1053/j.ajkd.2007.12.033

    Article  CAS  Google Scholar 

  22. Shimo-Nakanishi Y, Hasebe T, Suzuki A et al (2004) Functional effects of NAD(P)H oxidase p22(phox) C242T mutation in human leukocytes and association with thrombotic cerebral infarction. Atherosclerosis 175:109–115. doi:10.1016/j.atherosclerosis.2004.01.043

    Article  CAS  PubMed  Google Scholar 

  23. Zhu Y, Marchal CC, Casbon A-J et al (2006) Deletion mutagenesis of p22phox subunit of flavocytochrome b558: identification of regions critical for gp91phox maturation and NADPH oxidase activity. J Biol Chem 281:30336–30346. doi:10.1074/jbc.M607191200

    Article  CAS  PubMed  Google Scholar 

  24. Xu M, Chen X, Yan L et al (2008) Association between (AC)n dinucleotide repeat polymorphism at the 5′-end of the aldose reductase gene and diabetic nephropathy: a meta-analysis. J Mol Endocrinol 40:243–251. doi:10.1677/JME-07-0152

    Article  CAS  PubMed  Google Scholar 

  25. Li Y, Wang S (2010) Glycated albumin activates NADPH oxidase in rat mesangial cells through up-regulation of p47phox. Biochem Biophys Res Commun 397:5–11. doi:10.1016/j.bbrc.2010.04.084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Quintana LF, Guzmán B, Collado S et al (2006) A coding polymorphism in the 12-lipoxygenase gene is associated to essential hypertension and urinary 12(S)-HETE. Kidney Int 69:526–530. doi:10.1038/sj.ki.5000147

    Article  CAS  PubMed  Google Scholar 

  27. Krolewski AS, Gohda T, Niewczas MA (2014) Progressive renal decline as the major feature of diabetic nephropathy in type 1 diabetes. Clin Exp Nephrol. doi:10.1007/s10157-013-0900-y

    PubMed  PubMed Central  Google Scholar 

  28. Perkins BA, Krolewski AS (2005) Early nephropathy in type 1 diabetes: a new perspective on who will and who will not progress. Curr Diab Rep 5:455–463

    Article  PubMed  Google Scholar 

  29. Secrest AM, Becker DJ, Kelsey SF et al (2010) All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry. Diabetes Care 33:2573–2579. doi:10.2337/dc10-1170

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bedard K, Attar H, Bonnefont J et al (2009) Three common polymorphisms in the CYBA gene form a haplotype associated with decreased ROS generation. Hum Mutat 30:1123–1133. doi:10.1002/humu.21029

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Michelle Mollin for technical assistance. We are grateful to the University Joseph Fourier, the Faculty of Medicine, the Regional Clinical Research Department, DRCI and the Grenoble University Hospital.

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Author notes

    Authors and Affiliations

    1. Department of Nephrology, Nephrology Clinic, Grenoble University Hospital, Grenoble, 38043, France

      Benoit Franko, Thomas Jouve & Philippe Zaoui

    2. Chronic Granulomatous Disease Diagnosis and Research Centre, Therex-TIMC/Imag, UMR CNRS 5525, UJF-Grenoble 1, Université Grenoble Alpes, Grenoble, 38041, France

      Benoit Franko, Vincent Rzeoecki, Paul Semeraro & Marie José Stasia

    3. Department of Endocrinology, Grenoble University Hospital, Grenoble, 38043, France

      Pierre-Yves Benhamou & Laure Nasse

    4. UJF-Grenoble 1/CNRS/Clinical Research Centre-Inserm CIC03/TIMC-IMAG UMR 5525/Themas, Grenoble University Hospital, Grenoble, France

      Céline Genty

    5. CGD Centre, BEP/DBTP/Pôle Biologie, CHU de Grenoble, Grenoble, 38043, France

      Marie José Stasia

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    1. Benoit Franko
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    Corresponding author

    Correspondence to Benoit Franko.

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    The authors declare that they have no conflict of interest.

    Ethical standard

    All participants gave written consent before inclusion. The study was approved by the ethical committee (CPP Sud-Est V, Grenoble, France) and recorded in clinicaltrial.gov (NCT01371955).

    Human and animal rights

    All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

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    Informed consent was obtained from all patients for being included in the study.

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    Managed by Antonio Secchi.

    Marie José Stasia and Philippe Zaoui have contributed equally to this work.

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    Franko, B., Benhamou, PY., Genty, C. et al. RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up. Acta Diabetol 53, 469–475 (2016). https://doi.org/10.1007/s00592-015-0820-2

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    • DOI: https://doi.org/10.1007/s00592-015-0820-2

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