The intercellular adhesion molecule-1 (ICAM-1) gene polymorphism K469E in end-stage renal disease patients with cardiovascular disease

Abstract

The intercellular adhesion molecule-1 (ICAM-1) mediates interaction of activated endothelial cells with leukocytes. It plays an important role in the pathogenesis of atherosclerosis. A functionally important polymorphism of the ICAM-1 gene, K469E, has been described. We investigated whether this polymorphism influences the risk of CVD in end-stage renal disease (ESRD) patients. The groups of 1016 ESRD patients and 824 healthy individuals were genotyped by PCR and allele specific oligonucleotide technique. The T allele of the K469E polymorphism was significantly more frequent in ESRD CVD+ patients than CVD− and controls (OR 2.26, 95% CI 1.87–2.72 and 1.82, 95% CI 1.55–2.11, respectively). The TT genotype was also more frequent in CVD+ patients (OR 9.90, 95% CI 6.17–15.88 vs. CVD− subgroup). When patients were stratified according to clinical outcome of CVD, there was a tendency towards higher frequencies of the T allele and TT genotype in patients with myocardial infarction (OR for T allele 1, 57, 95% CI 1.12–2.18 vs. patients without MI). In the multivariate regression analysis the carrier status of T allele of K469E was an independent risk factor of susceptibility to CVD. Our data suggest that the ICAM-1 K469E polymorphism is associated with CVD in ESRD patients.

Introduction

The prevalence of cardiovascular disease (CVD) is much greater in patients with chronic renal failure than in general population [1], [2]. The high prevalence of CVD and increased mortality rate in this patient population can be only in part explained by traditional risk factors such as hypertension, diabetes mellitus, hyperlipidemia and age that are common in dialyzed patients with end-stage renal disease (ESRD) [3], [4], [5]. Inflammation has been shown to play an important role in CVD [6], [7]. It is possible that ESRD-associated dysfunction of the immune system has a direct impact on CVD progression.

Intercellular adhesion molecule-1 (ICAM-1), a cell surface glycoprotein, is a member of the immunoglobulin superfamily of adhesion molecules. It mediates adhesion of circulating leukocytes to the activated endothelium which is one of the earliest events in the pathogenesis of atherosclerosis [8], [9]. ICAM-1 is expressed on vascular endothelium, smooth muscle cells, macrophages and activated lymphocytes. Its expression can be upregulated by inflammatory mediators [10].

Several studies have documented an increase in expression of ICAM-1 on endothelial plaque in CHD, myocardial infarction and in patients undergoing coronary angioplasty [11], [12], [13].

The ICAM-1 gene is located on chromosome 19p13 and consists of seven exons [14]. The single nucleotide C to T polymorphism in the sixth exon of the ICAM-1 gene (K469E) results in an amino acid substitution from glutamic acid (E) to lysine (K) in immunoglobulin-like domain 5 of the ICAM-1 protein. This polymorphism has been reported to be involved in inflammatory diseases and atherosclerosis [15], [16], [17], [18].

The purpose of the present study was to determine whether the C/T polymorphism of the ICAM-1 gene is involved in cardiovascular disease in end-stage renal disease patients.