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The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-γ2 gene is suggested to associate with diabetic nephropathy and cardiovascular disease in type 2 diabetes. The aim of this study was to investigate the polymorphism in relation to diabetic nephropathy, end-stage renal disease (ESRD), mortality and cardiovascular (CVD) events in type 1 diabetic patients. This prospective observational follow-up study included 415 type 1 diabetic patients with overt diabetic nephropathy (252 men; age 42.2 ± 10.4 years [mean ± SD], duration of diabetes 28.3 ± 8.8 years, GFR 66 ± 8.8 ml/min) and 428 patients with longstanding type 1 diabetes and persistent normoalbuminuria (230 men; age 45.4 ± 11.6 years, duration of diabetes 27.8 ± 10.1 years). Follow-up: 8.1 (0.0–12.8) years (median [range]). There where no significant differences between cases and controls in genotype ( p = 0.51) or allele frequencies ( p = 0.25). Cox regression analysis revealed a covariate-adjusted hazard ratio (HR) for all-cause mortality in patients with the Ala/Ala genotype of 2.44 (1.23–4.84). The Pro12Ala polymorphism did not predict CVD events. However, the Ala/Ala genotype predicts ESRD (covariate-adjusted HR 2.60 (1.11–6.07)). Furthermore, Carriers of the Ala-allele had a higher rate of decline in GFR ( p = 0.040). In conclusion, the Pro12Ala polymorphism is not associated with type 1 diabetic nephropathy. The Ala-allele is associated with enhanced decline in GFR and predicts ESRD and all-cause mortality in patients with nephropathy.

Nitric oxide (NO) is important in the maintenance of vascular tone and regulation of blood pressure. NO may also play a role in the development of both nephropathy and cardiovascular disease (CVD) in patients with diabetes. The susceptibility to nephropathy and CVD depends to some extent on genetic factors, therefore polymorphisms in the gene coding for endothelial NO-synthase, NOS3, can affect the risk of developing these diseases. Type 1 diabetes patients attending the Steno Diabetes Center, Denmark, between 1993 and 2001 were enrolled in this study. A total of 458 cases with diabetic nephropathy (albumin excretion300 mg/24h) and 319 controls with persistent normoalbuminuria (30 mg/24h), despiteor =20 years of diabetes duration at follow-up were identified. Patients were followed until death or end of the study. Associations between seven NOS3-gene polymorphisms and nephropathy, progression of nephropathy and CVD were studied. There was significant association between the rs743507 TT-genotype and diabetic nephropathy. When including age at diabetes onset, diabetes duration at follow-up, baseline Hb(A1c), sex and ever smoking in the analysis the OR was 1.43 (95% CI=1.03-2.00), P=0.035. In analyses of CVD development using Cox-regression the rs1799983 GG-genotype was a significant protective factor in normoalbuminuric patients, HR=0.32 (0.12-0.82), P=0.018, but not in patients with macroalbuminuria (covariates were; age at follow-up, baseline Hb(A1c), baseline systolic blood pressure, baseline cholesterol, sex and ever smoking). Our conclusion is that the NOS3-gene may be involved in the development of diabetic nephropathy in patients with type 1 diabetes and can be predictive of CVD during follow-up.