Effects of apolipoprotein A5 haplotypes on the ratio of triglyceride to high-density lipoprotein cholesterol and the risk for metabolic syndrome in Koreans

Abstract

BackgroundSingle-nucleotide polymorphisms (SNPs) around the apolipoprotein A5 gene (APOA5) have pleiotropic effects on the levels of triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). APOA5 SNPs have also been associated with metabolic syndrome (MS). Here, we constructed haplotypes with SNPs spanning APOA5 and ZNF259, which are approximately 1.3 kb apart, to perform association analyses with the risk for MS and the levels of TG and HDL-C in terms of a TG:HDL-C ratio.MethodsThe effects of three constructed haplotypes (TAA, CGG, and CGA, in the order of rs662799, rs651821, and rs6589566) on the TG:HDL-C ratio and MS were estimated using multiple regression analyses in 2,949 Koreans and in each gender separately (1,082 men and 1,867 women).ResultsThe haplotypes, CGG and CGA, were associated with the TG:HDL-C ratio and the risk of MS development in both genders. That is, the minor alleles of the rs662799 and rs651821 in APOA5, irrespective of which allele was present at rs6589566, had the marked effects. Interestingly, a C–G–A haplotype at these three SNPs had the most marked effects on the TG:HDL-C ratio and the risk of MS development in women.ConclusionsWe have identified the novel APOA5-ZNF259 haplotype manifesting sex-dependent effects on elevation of the TG:HDL-C ratio as well as the increased risk for MS.

Peer Review #2 of "Functional polymorphisms of the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster are associated with dyslipidemia in a sex-specific pattern (v0.1)"

“…A genome-wide association study (GWAS) conducted in Chinese people (Zhou et al 2013) showed that rs651821 presented a strong association with TG levels. Cha S et al (Cha et al 2014) drew the conclusion that subjects carrying the variant allele of this SNP exhibited a higher risk of developing low-HDL cholesterolemia than noncarriers in both genders in Koreans, which was consistent with our findings. In our study, haplotype analysis showed that participants carrying the CGC haplotype of block 1 presented a higher risk of developing hypertriglyceridemia (OR=1.76, 95% CI=1.59-1.96) and reduced HDL (OR=1.80, 95% CI=1.59-2.03) than those carrying the CGT haplotype, which revealed that the T allele of rs651821 was associated with a higher risk of hypertriglyceridemia and reduced HDL.…”

Haplotype analysis of the Apolipoprotein A5 gene in Moroccan patients with the metabolic syndrome

“…Several studies performed association analysis using haplotypes constructed with SNPs located in different genes including APOA5. A particular haplotype determined by SNPs in APOA5 and ZNF259 genes, showed significant association with TG:HDL-C ratio and the risk of MS in both genders with marked effects in women [ 42 ]. Analysis of constructed haplotypes with SNPs in MTHFR, APOA5 and APOC3 genes, showed a highly significant association between one haplotype and MS in the Greek Population [ 43 ].…”

Prediction of cholesterol ratios within a Korean population

“…In addition, several studies have suggested that the rs6589566 could be a marker for the risk of coronary artery disease [ 34 – 36 ]. Moreover, the apolipoprotein A5 haplotypes, including rs6589566 , were implicated in the elevation of the TG/HDL-c ratio and the risk for metabolic syndrome in a Korean population [ 37 ].…”