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...

Singapore comprises three ethnic groups: Chinese (76.7%), Malays (14%), and Asian-Indians (7.9%). Overall, Singaporeans experience coronary heart disease rates similar to those found in the United States. However, there is a dramatic interethnic gradient, with Asian-Indians having significantly higher risk than Chinese and Malays. These differences are associated with HDL cholesterol levels and cannot be solely explained by environmental exposure, and may be driven by genetic factors. The gene encoding apolipoprotein A-V ( APOA5 ) has been located on chromosome 11, and it is emerging as an important candidate gene for lipoprotein metabolism. We investigated associations between APOA5 polymorphisms and plasma lipids in 3,971 Singaporeans to establish whether they accounted for some of the ethnic differences in plasma lipids. We found significant associations between the minor alleles at each of four common polymorphisms and higher plasma triglycerides (TGs) across ethnic groups. Haplotype analyses showed significant associations with TGs, explaining 6.9%, 5.2%, and 2.7% of the TG variance in Malays, Asian-Indians, and Chinese, respectively. Conversely, we observed significant inverse associations between the minor alleles and HDL cholesterol concentrations for Chinese and Malays. These data suggest that APOA5 plays a role in the ethnic differences observed for plasma TG and HDL cholesterol concentrations. -Lai, C-Q., E-S. Tai Singapore is a highly developed country in Southeast Asia, populated by ‫ف‬ 4.5 million people living in a mostly urbanized area of ‫ف‬ 700 km 2 and representing three ethnic groups (Chinese 76.7%, Malay 14%, and Indian 7.9%, with other minor ethnicities making up the other 1.4%). Despite their ethnic and cultural differences from Western populations, Singaporeans suffer from high cardiovascular disease (CVD) rates similar to those found in the United States and Australia (1). Most interestingly, the effects of urbanization have not affected all three major ethnic groups equally. Asian-Indians have the highest rate of CVD, followed at a significant distance by Malays and Chinese (1-4). In addition, the ethnic difference is further reflected by the diverse lipid profile among these ethnic groups. In particular, HDL cholesterol levels mirror CVD rates, with Asian-Indians having the lowest, followed by the Malays, and with the Chinese displaying the highest concentrations. Conversely, plasma triglyceride (TG) concentration is the highest in Malays and Asian-Indians and the lowest in Chinese. These differences occur despite the high socioeconomic status and the consumption of diets that have similar biochemical and nutritional compositions regardless of the ethnic origin (2,5). This provides an ideal situation in which to examine the contribution of genetic factors to disease risk heterogeneity and to study the interaction between genetic and environmental factors.High TG and LDL cholesterol and low HDL cholesterol concentrations are independent risk factors for CVD (6, 7). Identifying ...

Background-Apolipoprotein A5 gene (APOA5) variation is associated with plasma triglycerides (TGs). However, little is known about whether dietary fat modulates this association. Methods and Results-We investigated the interaction between APOA5 gene variation and dietary fat in determining plasma fasting TGs, remnant-like particle (RLP) concentrations, and lipoprotein particle size in 1001 men and 1147 women who were Framingham Heart Study participants. Polymorphisms Ϫ1131TϾC and 56CϾG, representing 2 independent haplotypes, were analyzed. Significant gene-diet interactions between the Ϫ1131TϾC polymorphism and polyunsaturated fatty acid (PUFA) intake were found (PϽ0.001) in determining fasting TGs, RLP concentrations, and particle size, but these interactions were not found for the 56CϾG polymorphism. The Ϫ1131C allele was associated with higher fasting TGs and RLP concentrations (PϽ0.01) in only the subjects consuming a high-PUFA diet (Ͼ6% of total energy). No heterogeneity by sex was found. These interactions showed a dose-response effect when PUFA intake was considered as a continuous variable (PϽ0.01). Similar interactions were found for the sizes of VLDL and LDL particles. Only in carriers of the Ϫ1131C allele did the size of these particles increase (VLDL) or decrease (LDL) as PUFA intake increased (PϽ0.01). We further analyzed the effects of n-6 and n-3 fatty acids and found that the PUFA-APOA5 interactions were specific for dietary n-6 fatty acids. Conclusions-Higher n-6 (but not n-3) PUFA intake increased fasting TGs, RLP concentrations, and VLDL size and decreased LDL size in APOA5 Ϫ1131C carriers, suggesting that n-6 PUFA-rich diets are related to a more atherogenic lipid profile in these subjects.