The 3′-UTR C > T polymorphism of the oxidized LDL-receptor 1 (OLR1) gene does not associate with coronary artery disease in Italian CAD patients or with the severity of coronary disease
Introduction
Functional changes of endothelial cells are implicated in the earliest stages of the pathogenesis of atherosclerosis. Accumulating evidence suggests that oxidized low-density lipoproteins (OxLDLs) play a critical role in the changes in endothelial function and in the accumulation of foam cells [1]. OxLDLs influence cellular properties principally by binding to specific receptors, the so-called “scavenger receptors” (SRs) [2]. Vascular endothelial cells internalize and degrade oxLDL through a putative receptor-mediated pathway that does not seem to involve the classical macrophage scavenger receptor. In 1997, Sawamura et al. [3] cloned the endothelial lectin-like oxidized LDL receptor 1 (OLR1 also known as LOX1), which is a type-II membrane protein that belongs structurally to the C-type lectin family of molecules, and is expressed in vivo in vascular endothelium and in vascular-rich organs.
OLR1 gene expression is enhanced in several pathological conditions, including hypertension, hyperlipidemia, diabetes and atherosclerosis [4]. OLR1 interacts with oxLDL, and not with native LDL, suggesting that OLR1 expression may be involved in atherogenesis. Moreover, recent investigations demonstrated that OLR1 is transcriptionally up-regulated by inflammatory cytokines, including TNF-α, interleukin-1, TGF-b, angiotensin II, endothelin-1 and by oxidative stress [5], [6].
Taken together, all this observations indicate that the OLR1 gene is dynamically regulated by various pathophysiological stimuli that are closely relevant to atherogenesis, and therefore represents a good candidate for coronary artery disease (CAD). Furthermore, there is strong evidence that OLR1 gene may play a role in the progression of atherogenesis associated with increased incidence of myocardial infarction and related to coronary plaque instability in myocardial infarction (MI) [7], [8].
The OLR1 gene is mapped to chromosome 12p13.1-p12.3. The coding sequence is divided into 6 exons by 5 introns. The first 3 exons correspond to the different functional domains of the protein (cytoplasmic, transmembrane and neck domains), and the residual 3 exons encode the carbohydrate-recognition domain, similar to other C-type lectin genes [9]. Previous studies have identified 7 novel polymorphisms in the OLR1 gene [10], [11], [12]. Among the 7 polymorphisms, 6 of them (located within introns 4, 5 and the 3′-UTR) were in complete linkage disequilibrium behaving as one polymorphism. For the K167N polymorphism in exon 4 controversial data have been reported: Mango and co-workers observed a weak association with acute myocardial infarction in an Italian population while Tatsuguchi et al. reported a positive association of this polymorphism with the risk of myocardial infarction in a sample of Japanese patients [7].
The 3′-UTR genetic variant in the OLR1 gene has been shown to be associated with severity of coronary stenosis in the Women's Ischemia Syndrome Evaluation (WISE) study, a population of women who were angiographically studied [11]. It was also demonstrated by electrophoretic mobility shift assay (EMSA) that this SNP was functional, determining a reduction in binding to transcription factors derived from aorta smooth muscle cells. Moreover, Mango et al. [10] showed that the same polymorphism in the 3′-UTR of the OLR1 gene, 188 C > T, was significantly associated with myocardial infarction in a group of 150 patients with MI, yielding an odds ratio of 3.74.
Since, the 3′-untraslated region of mRNA may be viewed as a regulatory region that is essential for the appropriate expression of many genes, we focused our interest on the 3′-UTR 188 C > T of the OLR1 gene. The aim of our study was therefore to investigate whether the 3′-UTR genetic variant in the OLR1 gene is a genetic risk marker of CAD in Italian patients with angiographically defined coronary atherosclerosis and to assess its relation with clinical and metabolic abnormalities, including severity of coronary artery disease (classified as presence of restenosis, single- or multiple coronary vessels disease, and MI).
Section snippets
Study subjects
A total number of 566 Caucasian subjects were studied. All subjects were recruited in the Centre-West Coast of Italy, most from Rome and its surrounding towns. The 351 coronary subjects were consecutively recruited among subjects undergoing coronary angioplasty or presenting with clear evidence of CAD (previous diagnosis of MI, or one or more stenoses greater than 50% in at least one major coronary artery after coronary catheterisation and clinical symptoms of angina). Diagnosis of MI was based
Study subjects
The clinical characteristics of the study subjects are shown in Table 1. By selection, CAD patients showed significantly higher frequencies of the classical coronary risk factors, such as male sex (P < 0.001), hypertension (P < 0.001), diabetes (P < 0.001), and dyslipidemia (P < 0.001). About half of the CAD subjects (49.6%) had a history of MI, and between those negative for MI, 23.1% reported typical symptoms of angina. The other underwent coronary angiography because of the presence of ischemic ECG
Discussion
In the present study no association between the 3′-UTR C > T SNP of the OLR1 gene and CAD in this Italian population was observed. Several lines of evidence support the potential role of OLR1 in atherosclerosis. OLR1 possesses a strong activity in binding, internalizing, and proteolytically degrading oxidized LDL [3]. OxLDL activation of OLR1 induces endothelial dysfunction/apoptosis [15], and OLR1 is dynamically up-regulated by pro-atherogenic conditions [16]. OLR1 is present in atheroma-derived
Acknowledgments
Financial support to this work was provided by the Faculty of Medicine (grant n. C26F022871) of the University of Rome “La Sapienza”, by the Italian Ministry of the University and Scientific Research (COFIN 2002), and by the Ministry of Health (grant RF2003) all to M.G. Baroni.
We wish to thank Dr Paolo Rubino and Dr Tullio Tesorio, Cardiac Catheterisation Unit, Casa di Cura Montevergine di Mercogliano (Av) for their participation to the study.
References (20)
Receptors for oxidized low density lipoprotein
Biochim Biophys Acta
(1999)- et al.
Diabetes enhances lectin-like oxidized LDL receptor-1 (LOX-1) expression in the vascular endothelium: possible role of LOX-1 ligand and age
Biochem Biophys Res Commun
(2001) - et al.
Transforming growth factor-b1 increases the expression of lectin-like oxidized low-density lipoprotein receptor-1
Biochem Biophys Res Commun
(2000) - et al.
Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction
Biochem Biophys Res Commun
(2003) - et al.
Oxidized low-density lipoprotein levels circulating in plasma and deposited in the tissue: comparison between Helicobacter pylori-associated gastritis and acute myocardial infarction
Am Heart J
(2004) - et al.
Oxidized low density lipoprotein (ox-LDL) binding to ox-LDL receptor-1 in endothelial cells induces the activation of NF-kB through an increased production of intracellular reactive oxygen species
J Biol Chem
(2000) - et al.
Induction of lectin-like oxidized LDL receptor by oxidized LDL and lysophosphatidylcholine in cultured endothelial cells
J Mol Cell Cardiol
(1999) Atherosclerosis – an inflammatory disease
N Engl J Med
(1999)- et al.
An endothelial receptor for oxidized low-density lipoprotein
Nature
(1997) - et al.
Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation
Circ Res
(1999)