Pronatriodilatin gene polymorphisms, microvascular permeability, and diabetic nephropathy in type 1 diabetes mellitus

Approximately 30% of diabetic patients develop nephropathy, the appearance of which is partially under genetic control. Atrial natriuretic peptide (ANP) has associated physiologic effects on the kidney. This study was conducted to examine the relationship between a newly identified and known polymorphism at the pronatriodilatin (PND) gene locus and renal involvement in type 1 diabetic subjects. Of 454 type 1 diabetic patients (219 men, 235 women), 323 showed no sign of nephropathy, 79 had incipient renal involvement, and 52 established nephropathy; 58 healthy control subjects were examined for comparison. Allele frequencies (C ⁷⁰⁸ versus T ⁷⁰⁸) were: 0.95 and 0.05 in normoalbuminuric patients, respectively; 0.88 and 0.12 in microalbuminuric patients; 0.96 and 0.04 both in those with overt nephropathy and in healthy control subjects (P = 0.011). Patients with incipient nephropathy were in disequilibrium compared with the total diabetic cohort (P = 0.02). In the same populations, an additional genotype for ScaI polymorphism of the PND gene was tested. The A ¹ and A ² allele frequencies were: 0.21 and 0.79 in normoalbuminuric patients; 0.13 and 0.87 in microalbuminuric patients; 0.06 and 0.94 in type 1 diabetic subjects with overt nephropathy; and 0.20 and 0.80 in healthy control subjects, respectively (P <0.0001). A subset of 55 normotensive patients with type 1 diabetes, well matched for clinical features, plasma ANP levels, and microvascular permeability to macromolecules, was investigated on the basis of the C ⁷⁰⁸/T and A ²/A ¹ polymorphisms. Both transcapillary escape rate of albumin (TER(alb)) and plasma ANP levels were significantly lower in patients with the T ⁷⁰⁸ than with C ⁷⁰⁸ allele, as well as in the A ¹ than in A ² allele (TER(alb): T ⁷⁰⁸ versus C ⁷⁰⁸:5.5 ± 1.7 versus 7.8 ± 2.0%/h, P = 0.0001; plasma ANP levels: 8.3 ± 3.9 versus 15.3 ± 7.7 pg/ml, P = 0.0003; A ¹ versus A ²:6.05 ± 2.2 versus 7.3 ± 2.1%/h, P = 0.044; 8.53 ± 4.6 versus 14.5 ± 7.4 pg/ml, P = 0.0024, respectively). Thus, in a large ethnically homogeneous cohort of diabetic subjects, our data show: (I) a significant association of C ⁷⁰⁸/T polymorphism with microalbuminuria in long-term diabetes and with both lower plasma ANP levels and widespread albumin leakage; and (2) a strong association between ScaI polymorphism and both diabetic nephropathy and plasma ANP concentrations. These results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.