Association Between Genetic Variations of Apo AI-CIII-AIV Cluster Gene and Hypertriglyceridemic Subjects (Molecular Pathology and Genetics‪)‬

Rather than single gene defect, impaired functions in two or more of the many genes that control lipid transport and metabolism have been suspected to cause inherited lipoprotein disorders or atherosclerosis. The apolipoprotein (apo) AI-CIII-AIV cluster gene is one of such groups. (5) The products of apo AI, CIII, and AIV genes, together with apo All, are the major protein components of high-density lipoproteins (HDLs). Each of them has been shown to modify the activity of lecithin:cholesterol acyltransferase in vitro [1, 2]. The gene coding for apo AI-CIIIAIV occurs in a tight cluster spanning ~15 kilobases on the long arm of human chromosome 11 [31, where the apo CIII gene is transcribed in the opposite direction to the apo AI and AIV genes. More than 10 common polymorphisms within the apo AI-CIII-AIV cluster gene have been detected [4,5], and several studies have suggested associations between some restriction fragment length polymorphism (RFLP) loci of this cluster gene and variations in plasma lipid concentrations [6, 7], although the results have not always been concordant in general populations. The apo AI-CIII-AIV cluster gene has been suggested to be very probably the cause of hyperlipidemia and atherosclerosis. For example, the rare allele of the SstI polymorphism in the 3' noncoding region of the apo CIII gene has mainly been associated with hypertriglyceridemia [8-13]. A few studies have also shown an increased frequency of the allele in patients with coronary artery disease (CAD) [14-16]. The rare allele of the XmnI polymorphism 5' of the apo AI gene appears to be a marker for familial combined hyperlipidemia (FCHL) [17,18] or hypertriglyceridemia [19]. The Pstl polymorphism has been reported to show an association with decreased HDL-cholesterol concentrations [20,21] and with angiographically detected premature CAD [22]. It has also been reported to show an association with apo AI concentrations in healthy subjects [20]. The two studies have indicated that the G to A mutation at by position 75 in the apo AI promoter is associated with increased concentrations of HDL-cholesterol [23,24]. These results therefore indicate that genetic variations in this cluster gene influence plasma lipid metabolism.