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
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.
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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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