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

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.

Neuropeptide Y gene polymorphisms are not associated with obesity in a South Indian population

“…Since then, this polymorphism has been linked to a number of disease conditions, hypertension (Karvonen et al, 2001;Pettersson-Fernholm et al, 2004), increased BMI (Ding et al, 2005;van Rossum et al, 2006), low-density lipoprotein cholesterol (Karvonen et al, 1998;Salminen et al, 2008), serum triglycerides Pihlajamaki et al, 2003), carotid atherosclerosis (Karvonen et al, 2001) type-I diabetes (Ma et al, 2007) and type-II diabetes (Niskanen et al, 2000;Ukkola and Kesaniemi, 2007). As NPY is a plausible candidate for obesity, we conducted a populationbased case-control study to investigate the association between NPY gene single-nucleotide polymorphisms (SNPs) and obesity.…”

Neuropeptide Y T1128C polymorphism

“…Thus, this work provides the first genetic evidence that NPY may be linked to altered cholesterol metabolism and that the polymorphism producing Pro (7) in the NPY signalling peptide may be one of the strongest genetic factors influencing serum cholesterol and LDL levels in obese subjects [16]. Subsequently, the Leu (7)-to-Pro(7) polymorphism has been linked to both type 1 [17] and type 2 diabetes [18,19], atherosclerosis [20] and coronary heart disease [21]. These studies suggest that the NPY T1128C polymorphism may be a strong independent risk factor for various cardiovascular diseases.…”

“…For example, it is unknown whether this T1128C polymorphism translates into higher or lower levels of active polypeptide NPY because serum or tissue NPY levels were either not measured or vary to a great extent between studies. Pettersson-Fernholm et al [17] found no differences in plasma NPY levels between type 1 diabetic patients with the T1128C allele and those with the wild-type genotype. By contrast, Kallio et al [26] reported significantly lower plasma NPY levels in subjects with the T1128C allele in healthy subjects.…”

“…There are several reasons why we should be cautious when a potential association between the T1128C polymorphism and cardiovascular risks is reported and its implications are interpreted. First, the frequency of the T1128C polymorphism shows a strictly geographical distribution, with most if not all positive associations found largely in Nordic countries such as Finland, Sweden and the Netherlands [9,[15][16][17][18][19][20][21]. In a recent retrospective study, Yamada et al [23] were unable to find an association between NPY T1128C polymorphism and myocardial infarction in Japanese subjects although the frequency of T1128C allele is low in that country.…”

Inflammatory effects of blood leukocytes: association with vascular function in neuropeptide Y proline 7-genotyped type 2 diabetes patients

“…15 In type 1 diabetes and hypertension patients, the Leu7Pro polymorphism has been associated with cardiovascular events. 16,17 NPY has many immunomodulatory functions: it regulates adhesion and cytokine secretion of T cells, 18,19 stimulates chemotaxis of monocytes 20 and modulates the functions of macrophages. 21 However, the precise role of NPY in the inflammatory cascade in atherosclerosis is not known.…”