The findings of the case-control and family-based studies demonstrate clearly that DNA sequence differences in eNOS influence the risk of advanced nephropathy in type 1 diabetes.

Cigarette smoking and poor glycemic control are risk factors for diabetic nephropathy in type 1 diabetes. However, the specifics of the relation of these risk factors to the onset of this complication have not been elucidated. To investigate these issues, we followed for 4 years 943 Joslin Clinic patients aged 15-44 years with type 1 diabetes who had normoalbuminuria during the 2-year baseline period. Microalbuminuria developed in 109 of the 943 individuals, giving an incidence rate of 3.3/100 person-years. The risk of onset of microalbuminuria was predicted somewhat more precisely by the measurements during the 1st and 2nd years preceding onset than by all the measurements during the longer (4-year) interval, suggesting attenuation of the impact of past hyperglycemia over time. Point estimates of the incidence rate (per 100 person-years) according to quartiles of HbA 1c during the 1st and 2nd years preceding the outcome were 1.3 in the 1st, 1.5 in the 2nd, 3.1 in the 3rd, and 6.9 in the 4th (P ‫؍‬ 1.3 ؋ 10 ؊9 ). Point estimates of the incidence rate (per 100 person-years) according to smoking status were 7.9 for current smokers, 1.8 for past smokers, and 2.2 for those who had never smoked (P ‫؍‬ 2.0 ؋ 10 ؊7 ). In a multiple logistic model, the independent effects of HbA 1c level and cigarette smoking remained highly significant, but their magnitudes were reduced. Using the same covariates in a generalized additive model, we examined the shape of the relationship between HbA 1c and onset of microalbuminuria and found significant nonlinearity in the logarithm of odds scale (P ‫؍‬ 0.04). The slope was steeper with HbA 1c >8% than <8%. Furthermore, the change in the slope was magnified among current smokers. In conclusion, patients with type 1 diabetes who smoke and have an HbA 1c >8% have the highest risk of onset of microalbuminuria.

In families with type 2 diabetes, UAE is a heritable trait, with a heritability similar to that for blood pressure. A significant genetic correlation between UAE and blood pressure, particularly in the presence of diabetes, indicates that these traits share common genetic determinants.

Risk of advanced diabetic nephropathy in type 1 diabetes is [1][2][3][4] and may contribute to the development of diabetic associated with endothelial nitric oxide synthase gene polymornephropathy [4, 5] and premature atherosclerosis [6]. phism.This abnormality results from a decreased availability of Background. Polymorphisms in the endothelial nitric oxide nitric oxide (NO), which can be caused by impaired NO synthase gene (eNOS) may be implicated in the development synthesis or to increased NO inactivation [7, 8].of nephropathy in patients with type 1 or insulin-dependent diabetes mellitus (IDDM). Synthesis of NO is catalyzed by three NO synthases:Methods. Three groups of IDDM patients were selected to endothelial, neuronal, and inducible [9]. Encoded by sepstudy this hypothesis: cases with advanced diabetic nephropaarate genes, each isoform has a distinct pattern of expresthy (N ϭ 78), cases with overt proteinuria but normal serum sion in tissues [10]. The endothelial NO synthase gene creatinine (N ϭ 74), and controls with normoalbuminuria de-(eNOS) encoding for endothelial NO synthase is a logical spite 15 years of diabetes (N ϭ 195). Parents of 132 cases and 53 controls were also examined and were used for the target for a search for DNA sequence differences that transmission disequilibrium test, a family-based study design may contribute to endothelial dysfunction and, indito test association. rectly, to the susceptibility to the development of diabetic Results. We examined four eNOS polymorphisms, and two nephropathy [1-4].were associated with diabetic nephropathy in the case-control