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

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.