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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



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).


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.


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.


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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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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Corresponding author

Correspondence to Benoit Franko.

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Conflict of interest

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 (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.

Informed consent

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

Additional information

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).

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  • Diabetic nephropathy
  • Type 1 diabetes
  • Genetic polymorphisms
  • CYBA
  • RAGE