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 (C708 versus T708) 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 A1 and A2 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 C708/T and A2/A1 
polymorphisms. Both transcapillary escape rate of albumin (TERalb) and plasma 
ANP levels were significantly lower in patients with the T708 than with C708 
allele, as well as in the A1 than in A2 allele (TERalb: T708 versus C708: 
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; A1 versus A2: 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: (1) a 
significant association of C708/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.