Association study of the thrombomodulin −33G>A polymorphism with coronary artery disease and myocardial infarction in Chinese Han population

Abstract

Background

Thrombomodulin (TM) is the anticoagulant endothelial cell membrane-bound protein cofactor in the thrombin-mediated activation of protein C. Recently, conflicting data have been reported regarding the possible contribution of the TM −33G>A polymorphism to coronary artery disease (CAD) or myocardial infarction (MI) in some Asian populations. We investigated this polymorphism in northern Han Chinese.

Methods

We performed a case-control study, including 808 patients with angiographically verified CAD or a history of an acute MI and 813 age- and sex-matched controls. The TM −33G>A polymorphism was determined by polymerase chain reaction and restriction fragment length polymorphism (PCR–RFLP) analysis.

Results

We did not find a significant difference in the frequency of the A allele between CAD patients (11%) and controls (9.8%; P=0.249), between MI patients (11.5%) and controls (P=0.163), or between premature MI patients (11.7%) and controls (P=0.265). Similarly, the difference of the genotypic distributions could be neglected across the groups: GG: (GA/AA) was 81.4%:18.6% in controls, 79.7%:20.3% in patients with CAD, 78.8%:21.2% in patients with MI, and 77.7%:22.3% in patients with premature MI, respectively (vs. controls, all P>0.05). The lack of association also persisted after adjusting for other conventional risk factors.

Conclusions

Our results seemed not to support a significant association of the TM −33G>A polymorphism with CAD, MI or premature MI in our population.

Introduction

Over the past few years, studies have focused on the role of haemostatic markers that reflect the inherited or acquired propensity to coronary artery disease (CAD) or myocardial infarction (MI), and several genetic mutations affecting coagulation proteins have been suggested as prothrombotic risk factors [1], [2]. Among these, a potential candidate is the thrombomodulin (TM) gene.

TM, the product of the TM gene, is an endothelial cell surface glycoprotein receptor that forms a high-affinity complex with thrombin. The thrombin-TM 1:1 complex rapidly activates protein C, which in turn, degrades the clotting cofactors activated factors (F) V and VIII. Moreover, thrombin bound to TM loses all its procoagulant activities. Thus, TM plays an important role in converting thrombin from a procoagulant to a physiological anticoagulant factor [3].

The −33G>A polymorphism in the 5′-promoter region of the TM gene was firstly identified by Ireland et al. [4]. Interestingly, the prevalence of the mutation A allele was more frequent in some Asians (8–10%) than in Caucasians (<1%) [4], [5], [6], [7], [8], [9]. Moreover, the GA/AA genotypes have been reported to be associated with decreased promoter activity, and increased risk for CAD or MI in both Taiwanese and Korean populations [6], [7], [8]. To our knowledge, a more recent study performed in Japanese did not replicate the above positive findings [9].

In view of these contradictory findings and the smaller sample sizes of the previously positive studies, we further investigated a possible association of the −33G >A polymorphism with CAD and MI in a relatively large Chinese Han population.