APOA5 genetic and epigenetic variability jointly regulate circulating triacylglycerol levels

Abstract

Apolipoprotein A5 gene (APOA5) variability explains part of the individual's predisposition to hypertriacylglycerolaemia (HTG). Such predisposition has an inherited component (polymorphisms) and an acquired component regulated by the environment (epigenetic modifications). We hypothesize that the integrated analysis of both components will improve our capacity to estimate APOA5 contribution to HTG. We followed a recruit-by-genotype strategy to study a population composed of 44 individuals with high cardiovascular disease risk selected as being carriers of at least one APOA5 SNP (-1131T>C and/or, S19W and/or 724C>G) compared against 34 individuals wild-type (WT) for these SNPs. DNA methylation patterns of three APOA5 regions [promoter, exon 2 and CpG island (CGI) in exon 3] were evaluated using pyrosequencing technology. Carriers of APOA5 SNPs had an average of 57.5% higher circulating triacylglycerol (TG) levels (P=0.039). APOA5 promoter and exon 3 were hypermethylated whereas exon 2 was hypomethylated. Exon 3 methylation positively correlated with TG concentration (r=0.359, P=0.003) and with a lipoprotein profile associated with atherogenic dyslipidaemia. The highest TG concentrations were found in carriers of at least one SNP and with a methylation percentage in exon 3 ≥82% (P=0.009). In conclusion, CGI methylation in exon 3 of APOA5 acts, in combination with -1131T>C, S19W and 724C>G polymorphisms, in the individual's predisposition to high circulating TG levels. This serves as an example that combined analysis of SNPs and methylation applied to a larger set of genes would improve our understanding of predisposition to HTG.