Atherosclerosis (ATH), as shown in coronary artery disease (CAD), is the underlying cause of cardiovascular disease (CVD).1 CVD remains a major global health burden,2 particularly in the United States3 and Asia,4 including Malaysia.5 ATH is a slow, progressing pathological process of plaque formation resulting from lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall.6 Susceptibility to ATH is influenced by the interaction of genetic and environmental factors.7,8 Despite the extensive study of ATH, a thorough understanding of the molecular genetic associations with ATH remains unknown.

Candidate gene association studies are an example of genome-wide association studies which have been extensively applied in genetic research.9,10 These association studies have been replicated across multiple populations and the results have identified numbers of single nucleotide polymorphisms (SNPs) associated with coronary artery disease.11 However, to reach a definitive conclusion, some of these association studies are best replicated in as many population studies as possible.

A problem with many published gene association studies is that a positive association observed in 1 report is often not reproducible in subsequent studies. This scenario may be due to inconsistently defined phenotypes, variability in sample size, and widely geographically different populations and ethnic groups under study. Indeed, SNPs allele frequencies can widely differ in different populations and study groups.12 However, identification of these variations could be the key to better understanding the disease, so that predicting risk, preventing, and managing CVD based on local evidence can be carried out with greater precision. In Malaysia, studies on the genetics of coronary artery disease are still limited.13 Additional data will be useful to help explain the pattern of the disease in a specific Malaysian population.14 Polymorphism of the full spectrum of genes associated with the pathophysiology of a disease is valuable information that could contribute significantly towards the management of the disease. Therefore, a comprehensive study concerning the genetic variations associated with ATH in Malaysia is highly recommended. Previously, a differential expression study on 11 candidate genes playing important roles in the initiation and modulation of atherosclerotic disease was conducted.15 These candidate genes carry out various roles in normal physiological function processes including those in the anticoagulation pathways,16 folate and homocysteine metabolism,17 plasma cholesterol concentration18 and maintaining blood vessel wall structure.19 Numerous reports suggest that different patterns in the upregulation or downregulation of the expression of these genes could contribute to the pathogenesis and the progression of ATH in tissue.

A differential expression study performed by the researchers in an earlier phase of this study showed that, from 11 genes, only LDLR, TP53 and MMP9 displayed notable results. The 3 genes exhibited significantly high expression in ACAT tissue samples compared to the NCAT.15 This finding suggests that these genes could be possible predictors for susceptibility in ATH development among Malaysians in this specific population. LDLR, TP53 and MMP9 genes were involved in cholesterol transport metabolism,15 cell death20 and breakdown of extracellular matrix,21 respectively. Thus, in this present study, we aimed to determine the polymorphisms of LDLR, TP53 and MMP9 genes associated with ATH in this Malaysian population.