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.
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.


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.
Pettersson-Fernholm
Kim
K
Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, and Folkhälsan Research Center, Biomedicum, University of Helsinki, Helsinki, Finland.
Karvonen
Matti K
MK
Kallio
Jaana
J
Forsblom
Carol M
CM
Koulu
Markku
M
Pesonen
Ullamari
U
Fagerudd
Johan A
JA
Groop
Per-Henrik
PH
D000328:Adult; D019943:Amino Acid Substitution; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood; D003327:Coronary Disease / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007930:Leucine; D008297:Male; D020125:Mutation, Missense; D009478:Neuropeptide Y / Q000235:genetics*; D011392:Proline; D011498:Protein Precursors / Q000235:genetics*; D011507:Proteinuria / Q000235:genetics*; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D002784:Cholesterol; D006442:Glycated Hemoglobin; D007930:Leucine; D009478:Neuropeptide Y; D011392:Proline; D011498:Protein Precursors; D014280:Triglycerides; C042084:preproneuropeptide Y