Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study

Abstract

Several polymorphisms in the APOA5 gene have been associated with increased plasma triglyceride (TG) concentrations. However, associations between APOA5 and lipoprotein subclasses, remnant-like particles (RLPs), and cardiovascular disease (CVD) risk have been less explored. We investigated associations of five APOA5 single-nucleotide polymorphisms (SNPs; ؊ 1131T Ͼ C, ؊ 3A Ͼ G, 56C Ͼ G IVS3 ؉ 476G Ͼ A, and 1259T Ͼ C) with lipoprotein subfractions and CVD risk in 1,129 men and 1,262 women participating in the Framingham Heart Study. Except for the 56C Ͼ G SNP, the other SNPs were in significant linkage disequilibria, resulting in three haplotypes (11111, 22122, and 11211) representing 98% of the population. SNP analyses revealed that the ؊ 1131T Ͼ C and 56C Ͼ G SNPs were significantly associated with higher plasma TG concentrations in both men and women. For RLP and lipoprotein subclasses, we observed gender-specific association for the ؊ 1131T Ͼ C and 56C Ͼ G SNPs. Female carriers of the ؊ 1131C allele had higher RLP concentrations, whereas in males, significant associations for RLPs were observed for the 56G allele. Moreover, haplotype analyses confirmed these findings and revealed that the 22122 and 11211 haplotypes exhibited different associations with HDL cholesterol concentrations.In women, the ؊ 1131C allele was associated with a higher hazard ratio for CVD (1.85; 95% confidence interval, 1.03 ؊ 3.34; P ‫؍‬ 0.04), in agreement with the association of this SNP with higher RLPs. Increased plasma triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and reduced high density lipoprotein cholesterol (HDL-C) concentrations are widely accepted as cardiovascular disease (CVD) risk factors (1-3). Their plasma concentrations are regulated by a combination of genetic and nongenetic factors. Whereas much emphasis has been placed on the identification of factors modifying the cholesterol fraction of lipoproteins, less weight has been placed on elucidating modifiers of TG concentrations. LPL has been traditionally considered as the major enzyme involved in plasma TG regulation (4). However, most of the genetic variability for plasma TG concentrations in the general population still remains unexplained. Therefore, other loci need to be identified to account for the bulk of the genetic variability corresponding to this phenotype. Recently, apolipoprotein A-V (apoA-V) has emerged as a significant player in plasma TG metabolism, as shown in several experimental animal models (5-8) and in human primary cell cultures (9). The evidence from mouse models consistently supports the role of apoA-V as an activator of LPL, thus increasing lipolysis and VLDL clearance (7,8). More recent evidence from a double-knockout mouse model supports the notion that the apoA-V ( APOA5 ) and apoC-III ( APOC3 ) genes independently influence plasma TG concentrations but in an opposing manner (10). However, less agreement exists regarding the potential effect of apoA-V in VLDL synthesis (7,8). Another line of evidence for the relev...

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

“…The BHS is a very comprehensively phenotyped resource, with the selected cohort having been followed up on average four times over 21 years with multiple metabolic measures, and thus was well-suited to addressing the aim of this study. Our cross-sectional association analyses confirmed previous findings of associations between the GCK rs1799884 variant and raised fasting glucose levels [9,22], the APOA5 rs662799 and rs3135506 variants and raised triacylglycerol levels [16,17,34], and the LPL rs328 variant and reduced triacylglycerol levels and raised HDL-C levels [20,21].…”

“…The variants selected were the apolipoprotein A-V (APOA5) single nucleotide polymorphisms (SNPs) rs662799 and rs3135506; the lipoprotein lipase (LPL) SNP rs328; and the glucokinase (GCK) SNP rs1799884, which have been shown in multiple cross-sectional studies to be associated with triacylglycerol (APOA5 and LPL) [16][17][18][19][20][21], HDL-C (LPL) [20,21] and fasting glucose (GCK) [9,22] levels, traits important in the risk of diabetes and cardiovascular disease.…”

A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese

“…5,30 It does so by reducing hepatic very low-density lipoprotein (VLDL) secretion and increasing VLDL metabolism. 2 There are reports of association of SNPs in the APOA5 gene with cardiovascular disease, including carotid atherosclerosis, 28 stroke 31 and coronary artery disease.…”

Apolipoprotein AV Accelerates Plasma Hydrolysis of Triglyceriderich Lipoproteins by Interaction with Proteoglycan-bound Lipoprotein Lipase

“…To observe lipoprotein particle turnover, human chylomicrons from apo-CII-deficient donors or mouse VLDLs from different genotypes were labeled in vitro with the non-degradable protein label 125 I-tyramine cellobiose as described previously (21). For turnover studies, anesthetized mice (7)(8) I-tyramine cellobiose VLDL or chylomicrons, respectively). Lipoprotein turnover was determined from 15 l of plasma 2, 5, 10, 20, and 30 min after injection.…”

“…Blood was obtained by retro-orbital bleeding 5 min later, and plasma was frozen at Ϫ80°C. Pre-and post-heparin plasma (5 l) were assayed using an artificial glycerol tri- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]oleate-containing lipid emulsion as described previously (22). To inhibit LPL activity of hepatic lipase, 1 M NaCl was added to independent samples.…”