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. Kim Pettersson-Fernholm, MD12,
  2. Matti K. Karvonen, DMSC3,
  3. Jaana Kallio, MD3,
  4. Carol M. Forsblom, DMSC12,
  5. Markku Koulu, DMSC3,
  6. Ullamari Pesonen, DMSC3,
  7. Johan A. Fagerudd, DMSC12,
  8. Per-Henrik Groop, DMSC12 and
  9. FinnDiane Study Group
  1. 1Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland
  2. 2Folkhälsan Research Center, Biomedicum, University of Helsinki, Helsinki, Finland
  3. 3Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
  1. 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

Abstract

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 (HbA1c 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 HbA1c (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.

Footnotes

  • M.K.K., M.K., and U.P. hold stock in Hormos Medical (Finland).

    • Accepted November 4, 2003.
    • Received June 27, 2003.
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  1. doi: 10.2337/diacare.27.2.503 Diabetes Care February 2004 vol. 27 no. 2 503-509
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