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Leucine 7 to Proline 7 Polymorphism in the Preproneuropeptide Y Is Associated With Proteinuria, Coronary Heart Disease, and Glycemic Control in Type 1 Diabetic Patients

¹ Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland
² Folkhälsan Research Center, Biomedicum, University of Helsinki, Helsinki, Finland
³ Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland

Address correspondence and reprint requests to Per-Henrik Groop, Folkhälsan Research Center, Biomedicum Helsinki (C318b), University of Helsinki, P.O. Box 63, FIN-00014, Finland. E-mail: per-henrik.groop{at}folkhalsan.fi

OBJECTIVE—Neuropeptide Y is a potent vasoconstrictor thought to enhance the development of atherosclerosis. The leucine 7 to proline 7 (Leu7Pro) polymorphism, located in the signal peptide part of the human preproneuropeptide Y, has been associated with serum lipid levels, intima-media thickness of the common carotid arteries, and diabetic retinopathy in type 2 diabetic patients. Therefore, we investigated the impact of the Leu7Pro polymorphism on diabetic nephropathy, cardiovascular risk factors, and cardiovascular disease in type 1 diabetic patients.

RESEARCH DESIGN AND METHODS—A total of 996 patients from the Finnish Diabetic Nephropathy study were studied in a case-control, cross-sectional study. The carrier frequency of the Pro7 substitution was 13% in the entire study population.

RESULTS—The Pro7 substitution was more common in patients with proteinuria than in those with a normal albumin excretion rate (16 vs. 11%, P < 0.05). Patients with the Pro7 allele had worse glycemic control (HbA_1c 8.8 vs. 8.5%, P < 0.005), more coronary heart disease (CHD) (14 vs. 8%, P < 0.05), and higher serum triglycerides (1.65 vs. 1.35 mmol/l, P < 0.005) than patients with the wild-type genotype. There were no differences in the plasma neuropeptide Y levels between the patients with Pro7 compared with those with the wild-type genotype. The Leu7Pro polymorphism was independently associated with HbA_1c (P < 0.001), proteinuria (P < 0.01), and CHD (P < 0.01) in multiple regression analyses.

CONCLUSIONS—We conclude that the Leu7Pro polymorphism may contribute to the genetic susceptibility to diabetic nephropathy and CHD in type 1 diabetic patients, possibly by influencing glycemic control and triglycerides.

Abbreviations: AER, albumin excretion rate • CHD, coronary heart disease • ESRD, end-stage renal disease • Leu7Pro, leucine 7 to proline 7 • NPY, neuropeptide Y • prepro-NPY, preproneuropeptide Y • RIA, radioimmunoassay

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