CD14 C(-260)T promoter polymorphism and prevalence of acute coronary syndromes Ramo ´n Arroyo-Espliguero a , Khaled El-Sharnouby a , Eugenia Va ´zquez-Rey a , Kamini Kalidas b , Steve Jeffery b , Juan Carlos Kaski a, * a Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St. George’s Hospital Medical School, Cranmer Terrace, London SW 17 ORE, UK b Medical Genetics Unit, Department of Clinical and Developmental Sciences, St. George’s Hospital Medical School, London, UK Received 25 June 2003; received in revised form 3 December 2003; accepted 25 December 2003 Available online 2 July 2004 Abstract Background: Inflammation and infection have been implicated in atherosclerosis and its complications. The CD14 receptor mediates monocyte activation by lipopolysaccharide (LPS) of Gram-negative bacteria. The aim of this study was to assess whether the C(-260)T polymorphism in the promoter of the CD14 receptor gene is associated with a higher prevalence of acute coronary syndromes (ACS) and severity of coronary atherosclerosis. Methods: We studied 428 patients (mean age: 63 F 10 years, 67% men) consisting of 334 patients with coronary artery disease (CAD) and 94 patients with normal coronary arteriogram. Patients with CAD were subdivided in two groups: (1) no previous history of ACS (n = 140; 64 F 9 years; 79% men) and (2) patients with a history of ACS (n = 194; 64 F 10 years; 80% men). CD14 genotypes were determined by a Polymerase Chain Reaction (PCR) – Restriction Fragment Length Polymorphism Analysis (RFLP) technique. Results: Patients with a prior ACS had a significantly higher frequency of the T/T genotype than CAD patients without prior ACS (33% vs. 20%; P = 0.009), even after multivariate analysis (odd ratio [OR] 1.8 [1.1 – 3.1]; confidence intervals [CI] 95%; P = 0.023). T/T genotype was not significantly different in CAD patients without prior ACS compared to controls (20% vs. 22.3%; P = 0.67), and there was no significant association between genotypes, or allele frequencies, and severity of CAD. Conclusions: The CD14 C(-260)T polymorphism is associated with a history of ACS and it may represent a genetically determined risk factor for the development of ACS and atheromatous plaque vulnerability in angina patients. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: CD14 receptor; Polymorphism; Coronary artery disease; Acute coronary syndromes; Angina pectoris 1. Background Studies have suggested that, in addition to well-estab- lished coronary artery disease (CAD) risk factors, infection by Gram-negative bacteria may have a pathogenic role in atherosclerosis [1,2]. Endotoxin or lipopolysaccharide (LPS), generated by Gram-negative bacteria activates mono- cytes [3], endothelial cells [4,5] and vascular smooth muscle cells [6]. LPS also increases plasma levels of low and very low-density lipoproteins (LDL and VLDL), contributes to LDL oxidation and decreases high-density lipoprotein (HDL) cholesterol levels [7]. Moreover, LPS promotes procoagulant activity by induction of tissue factor expres- sion in monocytes [8] and endothelial cells [9]. This array of processes are implicated in the development of atheroscle- rosis and acute events related to it [7]. CD14 receptor, a pattern recognition molecule on myeloid cells [10], is the main receptor for LPS [11]. Besides its role in host defence and innate immunity [12], CD14 is implicated in other biological functions such as monocyte activation [13], leukocyte – endothelial cell interactions [14] and regulation of apoptotic processes on both monocytes [15] and endothelial cells [16]. Chlamydial (Cp-) and human (hu-) heat shock protein 60 (HSP60) activate monocytes and monocyte-de- rived macrophages through CD14 receptors [17,18]. CD14 is not a trasmembrane protein, and signals are transduced via intracellular kinases, G-proteins, phospholipases [19,20] and CD14 coreceptors such as Toll-like receptors (TLRs) [21]. A common single nucleotide polymorphism (SNP) in the CD14 promoter has been proposed to be associated with 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.12.015 * Corresponding author. Tel.: +44-20-8725-5901; fax: +44-20-8725- 3328. E-mail address: jkaski@sghms.ac.uk (J.C. Kaski). www.elsevier.com/locate/ijcard International Journal of Cardiology 98 (2005) 307 – 312