Elsevier

Atherosclerosis

Volume 183, Issue 2, December 2005, Pages 336-341
Atherosclerosis

The peroxisome proliferator-activated receptor delta +294T/C polymorphism in relation to lipoprotein metabolism in patients with diabetes mellitus type 2 and in non-diabetic controls

https://doi.org/10.1016/j.atherosclerosis.2005.03.016Get rights and content

Abstract

Objective

Peroxisome proliferator-activated receptor δ (PPARδ) is an ubiquitously expressed transcription factor that has been implicated in the regulation of genes related to cholesterol metabolism. Conflicting results exist regarding the association of the recently described +294T/C polymorphism in the 5′-untranslated region (5′-UTR) in exon 4 of the PPARδ gene and plasma lipoprotein concentrations. Purpose of the present study was to examine for the first time in a German population and for the first time also in women the presence of a potential association between the aforementioned polymorphism and lipoprotein concentrations in patients with diabetes mellitus type 2 (DM-2) and in non-diabetic controls. Furthermore, a possible gene–gene interaction between the PPARδ +294T/C polymorphism and the PPARα L162V polymorphism was examined.

Design and methods

We determined by PCR the polymorphism in a total of 402 patients with DM-2 (230 men and 172 women) and in 436 healthy controls (248 men and 188 women) from the LIANCO study (lipid analytic cologne).

Results

The genotype distribution was not different between DM-2 and controls (+294TT 65.6% versus 66.7%, +294TC 30.5% versus 29.4%, +294CC 3.9 versus 4.0%, respectively). There was no difference in the low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) or triglyceride (TG) concentrations between carriers and non-carriers of the rare C allele in the DM-2 population. In specific, the heterozygotes for the C allele had LDL-C concentrations of 157 ± 80 mg/dl, HDL-C of 54 ± 17 mg/dl and TG of 273 ± 507 mg/dl, while the C allele homozygotes had concentrations of LDL-C 149 ± 44 mg/dl, HDL-C of 59 ± 21 mg/dl and TG of 197 ± 110 mg/dl. The LDL-C, HDL-C and TG concentrations of TT homozygotes were 156 ± 49 mg/dl, 56 ± 18 mg/dl and TG 225 ± 242 mg/dl, respectively. The same lack of association was present in the non-diabetic controls, both in men and in women. There was no association between the genotypes and body mass index. Furthermore, no gene–gene interaction between the PPARδ +294TC and the PPARα L162V polymorphism was observed regarding lipoprotein concentrations and atherosclerotic disease.

Conclusions

The data suggest that the PPARδ +294T/C polymorphism has no influence on plasma lipoprotein concentrations, body mass index or atherosclerotic disease either in healthy subjects or in patients with DM-2, both in males and females.

Introduction

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the regulation of lipid and glucose metabolism, in inflammation, embryo implantation [1] and cancer [2]. There are three distinct PPAR isoforms, namely PPARα, PPARδ (or PPARβ) and PPARγ. PPARs bind to sequence-specific DNA response elements as a heterodimer with the retinoic acid receptor [3]. PPARδ is ubiquitously expressed, often at higher levels than the two other PPARs [4]. Higher levels of expression are seen in tissues with active lipid metabolism, such as adipose tissue, small intestine, heart and skeletal muscle.

PPARδ is activated by long chain fatty acids, prostacyclin and the peroxisome proliferator activator WY14643 [5] as well as by other synthetic molecules described recently [6], [7]. However, the function of PPARδ has not been completely clarified. Recently, it was demonstrated that activation of PPARδ promotes fatty acid oxidation and utilization in adipocytes and skeletal muscle cells, suggesting a role of PPARδ as a regulator of fat burning [8]. Furthermore, in vitro studies using a PPARδ agonist showed that PPARδ activation promotes lipid accumulation in macrophages and increases the expression of genes involved in lipid uptake and storage [9]. It has also been shown that a selective PPARδ agonist increases plasma cholesterol concentrations, decreases plasma triglyceride (TG) concentrations, increases high density lipoprotein cholesterol (HDL-C) and decreases the fraction of small and dense low density lipoprotein cholesterol (LDL-C) in obese rhesus monkeys [10].

Recently, a PPARδ polymorphism in the 5′-untranslated region (5′-UTR) at position +294 in exon 4 has been associated with cholesterol metabolism in male subjects, although with conflicting results [11], [12]. Since genetic association studies are in need of replication, and because of the conflicting results, the purpose of the present study was to examine whether the +294T/C polymorphism plays a role in lipoprotein metabolism in German healthy subjects as well as in patients with type 2 diabetes (DM-2). For the first time also a female population was investigated. In addition, since the PPARα polymorphism L162V has been associated with a lower prevalence of atherosclerotic disease [13], a possible gene–gene interaction between the two polymorphisms was investigated.

Section snippets

Study population

A total of 838 subjects (age 63 ± 11, range 20–88 years) were included in the study. Their data were obtained from the LIANCO database (Lipid Analytic Cologne). The study protocol had been approved by the university ethics committee and all subjects gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki in its current revision. In brief, LIANCO was designed to assess the relationship among genetic mutations, serum lipoproteins, other biochemical

Results

Genotyping was performed in 436 controls and in 402 patients with DM-2. The genotype frequencies were 65.6 and 66.7% +294TT, 30.5 and 29.4% +294TC, 3.9 and 4.0% +294CC for the controls and the DM-2 group, respectively (Table 1). The polymorphism was found to be in Hardy-Weinberg equilibrium (HWE) as calculated by chi-square test comparing the observed numbers of PPARδ genotypes with those expected for a population in HWE (chi square p = 0.86). The frequency of the rare C-allele was 0.189 in the

Discussion

PPARδ is expressed ubiquitously but its function has not been clarified yet. Recently, the +294T/C polymorphism in the 5′-UTR of PPARδ in exon 4 has been implicated in cholesterol metabolism in Swedish men [12]. Homozygotes for the rare C allele had higher plasma LDL-C concentrations than homozygotes for the common T allele, while there were no associations with the HDL-C levels. Interestingly, the same group of investigators showed in another study in Scottish men from the WOSCOPS trial that

Acknowledgement

This project was funded by Lipid Analytic Cologne (LIANCO), supported by Bayer Vital GmbH, Leverkusen (Germany) and by the Köln Fortune Programme, University of Cologne (Germany). We would like to thank Mrs. Nadine Spenrath and Mrs. Doris Vollmar for their excellent technical assistance. Furthermore, we would like to thank the Kämpgen Stiftung (Cologne, Germany) for their support for the acquisition of equipment necessary for the performance of this study.

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