Absence of Association Between CD86 +1057G/A Polymorphism and Coronary Artery Disease

Introduction

A therosclerosis is a chronic inflammatory response in the walls of arteries, which results in the so-called endothelial dysfunction (Ross, 1999). Emerging evidence has shown that the presence and extent of endothelial dysfunction is extremely related to the outcome of patients with coronary artery disease (CAD) (Schachinger et al., 2000; Suwaidi et al., 2000; Heitzer et al., 2001). CAD is forecast to be one of the most common causes of mortality and morbidity and affects a considerable portion of the society (Ahmad and Bhopal, 2005; Apikoglu Rabus et al., 2008). The disease is also the most common reason for death of men and women over 20 years of age (American Heart Association, 2009). The mortality rates of CAD are increasing alarmingly in developing countries including China, although it decreased in economically developed country (Yusuf et al., 2001; Sanderson et al., 2007; Rosamond et al., 2008). The risk of developing CAD is influenced by a number of factors, including hypertension, high low-density lipoprotein cholesterol (LDL-C), low levels of high-density lipoprotein cholesterol, diabetes mellitus, creatinine, dietary fat consumption, cigarette smoking and physical inactivity, as well as genetic factors (Grundy et al., 1998; Nordlie et al., 2005; Vinukonda et al., 2009). For example, Vinukonda et al. (2009) found single-nucleotide polymorphisms of methylene tetrahydrofolate reductase and glutamate carboxypeptidase II to be associated with risk for CAD.

CD86 is well known for the crucial role it plays in the initial immune response due to its presence in the initial phases of T-cell activation (Odobasic et al., 2008). Additionally, CD86 has been implicated in a wide variety of processes, including innate immune response, allergic inflammation, host immune responses, and chronic lymphocytic leukemia (Zhang et al., 2007; Dai et al., 2009; Nolan et al., 2009; Pereira et al., 2009). Recently, several studies have reported that CD86 is differentially expressed on the microvasculature, macrophages, and foam cells from subjects with atherosclerosis (Hagg et al., 2008; Lozanoska-Ochser et al., 2008). Importantly, CD86 is upregulated in cultured monocyte-derived dendritic cells of patients with CAD (Dopheide et al., 2007). These results suggest that CD86 may play critical roles in the development of CAD.

CD86 gene, a single-copy gene, is located on chromosome 3q21 in humans. The CD86 gene consists of eight exons. Exons 7 and 8 encode the cytoplasmic tail of the CD86 molecule (Jellis et al., 1995). A polymorphism at position codon 304 located in exon 8 (a G to A transition at position +1057) results in an alanine to threonine substitution (Delneste et al., 2000). Previously, several studies have investigated the relationship of CD86 +1057G/A polymorphism and a range of human diseases, such as asthma (Corydon et al., 2007), rheumatoid arthritis, systemic lupus erythematosus (Matsushita et al., 2000), diabetes (Turpeinen et al., 2002), liver transplantation (Marin et al., 2005), and sarcoidosis (Handa et al., 2005).

To date, no study has examined the association between CD86 polymorphism (rs1129055) and risk of CAD. Therefore, the purpose of this study was to investigate whether CD86 polymorphism is related to CAD in a Chinese population.

Materials and Methods

Results

The genotype and allele frequencies of CD86 gene polymorphism in CAD patients and controls are shown in Table 2. The genotype distribution between the controls and cases were in agreement with Hardy–Weinberg equilibrium. There was no significant difference in the genotype distribution and allele frequency of the CD86 +1057G/A polymorphism (rs1129055) between the cases and controls.

Discussion

CAD is expected to be the main cause of death globally in 2030 owing to a rapidly increasing prevalence in developing countries (Okrainec et al., 2004; Mathers and Loncar, 2006). Recently, growing evidence has shown that inflammation is a critical factor in all stages of CAD process, including atherosclerosis, plaque destabilization, plaque rupture, and postischemia damage to the myocardium (Ross, 1999; Hansson, 2005), and costimulatory molecules may regulate inflammation in innate immunity via macrophage/neutrophil contact (Kopf et al., 1999; Nolan et al., 2009).

CD86, one of the key costimulatory molecules, is involved in the initiation of T-cell immunity. Specifically, it has been identified that CD86 is expressed by antigen-presenting cells such as dendritic cells and macrophages (Salomon and Bluestone, 2001). CD86 can induce T-cell activation, proliferation, and differentiation and promote secretion of inflammatory factors by binding to CD28 (Roitt et al., 2001). In contrast, CD86 negatively regulates T-cell proliferation and suppresses ongoing T-cell responses by binding to CTLA4 (Krummel and Allison, 1995; Waterhouse et al., 1995). CTLA4, a homolog of CD28, has higher affinity for CD86 than CD28 molecules and is mainly expressed on activated T cells (Salomon and Bluestone, 2001; Corydon et al., 2007).

In addition to the costimulatory role of CD86 in T-cell activation and signaling, it also plays important roles in the development of cardiovascular diseases. Lozanoska-Ochser et al. (2008) detected the expression and function of costimulatory molecules by human islet endothelial cells and found that CD86 expression on the microvasculature facilitated T-cell adhesion and migration. Buono et al. (2004) reported that the absence of B7-1 and B7-2 in LDL receptor (LDLR)-deficient mice developed decreased atherosclerosis compared with B7-1/B7-2-expressing control mice. However, Ait-Oufella et al. (2006) reported that LDLR^−/− mice receiving bone marrow from CD80^−/−CD86^−/− mice grew large-sized atherosclerotic lesion in the aortic root, suggesting negative correlation between the presence of T_reg cells and the development of atherosclerosis. Moreover, Dopheide et al. (2007) reported a higher expression of CD86 molecule in patients with CAD compared with healthy controls, and this significant difference may contribute to the pathophysiological processes in atherogenesis.

On the basis of these previous studies showing the important roles of CD86 in the development of CAD, we hypothesized that CD86 polymorphism may be involved in the pathogenesis of CAD. However, we failed to find any association between CD86 +1057 G/A polymorphism and CAD in a Chinese population. In concordance with our study, Corydon et al. (2007) reported that no evidence of association between +1057 G/A polymorphism in CD86 and asthma was observed in a Danish population. Matsushita et al. (2000) found no significant difference between the +1057G/A polymorphism and patients with sarcoidosis, rheumatoid arthritis, and systemic lupus erythematosus in a Japanese population (Handa et al., 2005). Additionally, Turpeinen et al. (2002) found no association between the exon 8 polymorphism and type I diabetes. In contrast, Marin et al. (2005) found that recipients carrying the A allele or the AA genotype had a decreased risk of acute rejection, and patients carrying the AA genotype revealed a higher graft survival rate (83.3%) than those carrying the GA genotype (49.3%) or GG genotype (56.5%).

In conclusion, this is the first study that investigated the relationship of CD86 gene polymorphism with the occurrence of CAD. However, we found no association between CD86 gene polymorphism and CAD in a Chinese population. Our study had 84% power to detect an effect with an estimated relative risk of 1.8 in the subjects of CAD patients and control group under a dominant genetic model. Additional studies with larger samples in diverse ethnic populations will be of great value to confirm this finding.