Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with type 1 diabetes.

Increased production of reactive oxygen species (ROS) in diabetes is thought to play a major role in the pathogenesis of diabetic microvascular complications such as nephropathy and retinopathy. The NAD(P)H oxidase complex is an important source of ROS in the vasculature. The p22 subunit is polymorphic with a C242T variant that changes histidine-72 for a tyrosine in the potential heme binding site, together with a A640G in the 3' untranslated region. The aim was to investigate the frequency of these polymorphisms in 268 patients with type 1 diabetes with or without microvascular complications. There was a highly significant increase in the frequency of the T/T242 genotype in patients with nephropathy compared with those with retinopathy alone or no microvascular disease after 20 years' diabetes duration (uncomplicated) or normal healthy control subjects (33.3 vs. 6.5, 5.7, and 0.0%, respectively, P < 0.000001). Furthermore, the T242/G640 haplotype was found in 39.4% of the patients with nephropathy but in only 26.5% of the patients with retinopathy and 15.3 and 10.6% of the uncomplicated and normal control subjects, respectively. When these variants of NAD(P)H oxidase were analyzed together with aldose reductase (5'ALR2) susceptibility genotypes, >46.0% of the patients with nephropathy possessed a T242 allele with the Z-2 5'ALR2 allele compared with only 11.2% of the uncomplicated patients (P < 0.00003). In conclusion, these results suggest NAD(P)H oxidase together with the polyol pathway may contribute to the pathogenesis of diabetic nephropathy.