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 (AN P) has associated physiologic effects on the kidney. This study was conduct ed to examine the relationship between a newly identified and known polymor phism at the pronatriodilatin (PND) gene locus and renal involvement in typ e 1 diabetic subjects. Of 454 type 1 diabetic patients (219 men, 235 women) , 323 showed no sign of nephropathy, 79 had incipient renal involvement, an d 52 established nephropathy; 58 healthy control subjects were examined for comparison. Allele frequencies (C-70S versus T-70S) 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 health y 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 g ene 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; 0.0 6 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 5 5 normotensive patients with type 1 diabetes, well matched for clinical fea tures, 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 (TERa1b) and plasma ANP levels w ere 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 (TERa1b: 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; Al 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 = 0.002 4, respectively). Thus, in a large ethnically homogeneous cohort of diabeti c subjects, our data show: (I) a significant association of C-708/T polymor phism with microalbuminuria in long-term diabetes and with both lower plasm a ANP levels and widespread albumin leakage; and (2) a strong association b etween ScaI polymorphism and both diabetic nephropathy and plasma ANP conce ntrations. These results suggest a possible role of PND gene in conferring protection from nephropathy and microvascular damage in type 1 diabetes.