Introduction

Coronary artery disease (CAD), a multifactorial heart disorder resulting from all kinds of predisposing environmental and genetic factors [1], is still one of the leading causes of disability and death around the world, accounting for 14.8% of global death [2]. Premature coronary artery disease (PCAD) is defined as CAD that occurs in males <55 years old or females <65 years old [3]. Even though PCAD constitutes only about 30% of all CAD subjects [4], [5], it is highly stressful for the patients’ families and generates a heavy social burden because of the longer period that the patient lives with the disease in comparison to older patients with CAD [6]. Large epidemiological studies have revealed that genetic factors have a strong influence on early onset CAD [7]. One known factor is the apolipoprotein E (APOE) gene [8].

Apolipoprotein E (apoE) is a multifunction glycoprotein containing 299 amino acids, which are encoded by the APOE gene [9]. It acts as cholesterol carrier and plays a major role in mediating the transportation and metabolism of lipids [10]. The APOE gene is situated at 19q13.2 of the human chromosome and has four exons and three introns [11]. As the genetic polymorphisms which are most widely studied in APOE, rs429358 and rs7412 together define the ε۲, ε۳, and ε۴ alleles, which encode three major protein isoforms (E2, E3, E4) and generate six different genotypes (ε۲/۴, ε۲/۳, ε۳/۴, ε۳/۳, ε۲/۲, ε۴/۴) [۱۲]. There is significant discrepancy in structure and function among the three protein isoforms [12]. ε۳ is the wild type, and its amino acids at positions 112 and 158 are cysteine and arginine, respectively [10]. It has normal affinity for low-density lipoprotein receptors (LDLR) and modulates the clearance of lipoprotein remnants from the plasma [12]. When the 112th amino acid is replaced by arginine, ε۳ mutates into ε۴٫ Similarly, ε۳ mutates into ε۲ when the 158th amino acid is replaced by cysteine [13]. ε۴ has similar high affinity for LDLR as ε۳ and enhanced binding capacity for lipids, so it impairs the process of lipolysis and is associated with high levels of very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and total cholesterol [12]. As for ε۲, it has defective affinity ability for LDLR, which would delay the clearance of VLDL. ε۲ is associated with low levels of LDL and total cholesterol [12].