Single-nucleotide polymorphisms (SNPs) in the apolipoprotein A5 gene (APOA5), located on chromosome 11q23 near the APOA1–C3–A4 gene cluster, have pleiotropic effects on changes in the levels of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) [1, 2]. Recently, a genome-wide association study (GWAS) reported that the minor allele of a SNP, rs964184, has a bivariate effect on TG-elevation and HDL-C-decrease . These pleiotropic bivariate associations of APOA5 SNPs, in turn, affect the risk for metabolic syndrome (MS) [1, 2, 4].
Haplotype analyses of association of APOA5 SNPs with lipid levels and risk for MS have focused primarily on variants located within APOA5 or within the APOA1–C3–A4–A5 gene cluster [5–12]. In particular, the APOA5 haplotypes, APOA5*1, and *2, and *3, comprised of rs662799 (-1131T>C), rs3135506 (56C>G), rs2072560 (IVS3 + 476G>A), and rs2266788 (1259T>C), have been studied for association with lipid levels and MS [5, 11–13]. The APOA5*2 haplotype, determined by the minor alleles of rs662799, rs2072560, and rs2266788, has been associated with elevated TG levels and risk for the development of MS [11–13], while the APOA5*3 haplotype, determined by the minor allele of rs3135506, has been shown to associate with increased levels of TG [4, 5].
However, APOA5 is adjacent to the zinc finger protein 259 gene (ZNF259; approximately 1.3 kb downstream of APOA5), so that separation of the effects of these closely located genes is difficult. In fact, it is possible that crosstalk between APOA5 and ZNF259 contributes to modulation of plasma TG levels. Although the precise mechanisms associated with this have yet to be determined, research has indicated that APOA5 interaction with proteoglycan-bound lipoprotein lipase and with low-density lipoprotein receptor can reduce plasma TG levels by hydrolysis of TG-rich lipoproteins and by endocytosis of remnant lipoproteins, respectively . ZNF259 encodes a zinc finger protein ZPR1 that binds to the cytoplasmic tyrosine kinase domain of epidermal growth factor receptor (EGFR) in quiescent cells . When mitogens such as EGF disrupt ZPR1 binding by tyrosine phosphorylation of EGFR, ZPR1 is translocated to the nucleus. It has been reported that remnant lipoproteins, among TG-rich lipoproteins, induce EGFR phosphorylation in smooth muscle cells, which results in smooth muscle cell proliferation and atherosclerosis risk  and that EGF concentrations in plasma and peripheral blood mononuclear cells associate with lipid concentrations, including TG and HDL-C . Furthermore, the variants exerting effects on TG and HDL-C levels, including rs662799, rs3135506, rs651821, rs2072560, rs2266788, rs6589566, and rs964184, cluster together and are in strong linkage disequilibrium (LD) with each other around the two genes [3, 18, 19]. Therefore, construction of haplotypes with variants spanning both genes is necessary to estimate the precise TG-elevating and HDL-C-lowering effects of APOA5 SNPs in a population.
The current study aimed to determine the effects of haplotypes constructed from variants located around APOA5 and ZNF259 on the levels of TG and HDL-C, in terms of a ratio of TG to HDL-C, as well as on the risk for MS development. Due to the stronger effects of TG levels on risk of coronary disease in the context of HDL-C levels  and the high correlation between the levels of TG and HDL-C, the TG:HDL-C ratio can be a more efficient predictor of the risk for coronary artery diseases [21, 22]. In addition, sex-dependent association patterns of these haplotypes were evaluated due to the reported gender effect of APOA5 haplotypes on MS risk .