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Pronatriodilatin Gene Polymorphisms, Microvascular Permeability, and Diabetic Nephropathy in Type 1 Diabetes Mellitus

MONICA NANNIPIERI^*, GIUSEPPE PENNO^*, LAURA PUCCI^*, HELEN COLHOUN, CORRADINO MOTTI, ANNA BERTACCA^*, LOREDANA RIZZO^*, LAMBERTO DE GIORGIO^§, GIAMPAOLO ZERBINI^||, RUGGERO MANGILI^|| and RENZO NAVALESI^*

^* Department of Endocrinology and Metabolic Disease, University of Pisa, Italy
Department of Epidemiology and Public Health, University College London, London, United Kingdom
Department of Internal Medicine, University of Roma "Tor-Vergata," Rome, Italy
^§ La Spezia Hospital, La Spezia, Italy
^|| Department of Medicine, University of Milan, San Raffaele Scientific Institute, Milan, Italy.

Correspondence to Dr. Monica Nannipieri, Dipartimento di Medicina Interna Università degli Studi di Pisa ed Unità Metabolica dell'Istituto di Fisiologia Clinica del C.N.R., Via Savi 8, 56100 Pisa, Italy. Phone: +39 50 583230; Fax: +39 50 553235; E-mail: nannipi{at}nsifc.ifc.pi.cnr.it

Abstract. 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 (TER_alb) 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 (TER_alb: 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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673