Hypertriglyceridemia: Interaction between APOE and APOAV Variants

Schaefer et al. (1) recently reported an association between a distinct combination of variants in the apolipoprotein E (APOE) and APOAV genes and hypertriglyceridemia. Among 170 hypertriglyceridemic (HTG) patients, all carriers of APOE22 (n = 7) had at least 1 APOAV Trp19 allele, but this combination was not found in controls with triglyceride (TG) concentrations within the reference interval. APOE is a structural component of TG-rich lipoproteins; it serves as a ligand for lipoprotein receptors and plays an important role in the catabolism of remnant particles (2)(3). Of the 3 common apoE isoforms, apoE4 (Cys112>Arg) and apoE2 (Arg158>Cys) differ from the commonest isoform, apoE3, by a single amino acid substitution. The APOE4 allele has been shown to be associated with increased plasma cholesterol and with an increased risk of coronary heart disease. In contrast, the APOE2 allele is associated with low plasma concentrations of cholesterol and is believed to be protective against coronary heart disease [reviewed in Refs. (2)(3)]. APOAV variants (e.g., T−1131>C and Ser19>Trp) play an important role in modulating plasma TG concentrations in humans (4). An association between the APOAV Ser19>Trp polymorphism and TG concentrations has been found in many population samples, but the total impact of this variant is not the same in different ethnic groups (4)(5)(6)(7). The Trp19 allele was found to be associated with extremely high concentrations of plasma TG (8), and Trp/Trp homozygotes have a higher risk of myocardial infarction (6). Recently, it was reported that apoAV interacts physically with lipoprotein lipase and significantly increases its activity (9). Computational analysis of the apoAV protein suggests that the change of Ser19 to Trp could lead to impaired export of apoAV from the liver (10). Using a previously described method, we have analyzed (by PCR and restriction analysis) APOE and APOAV variants (T−1131>C, Ser19>Trp, and Val153>Met) (6)(11) in 2559 unrelated Caucasians. This population sample included 1191 males [mean (SD) age, 49.2 (10.8) years; TGs, 2.0 (1.3) mmol/L; total cholesterol, 5.8 (1.0) mmol/L; body mass index, 28.2 (4.0) kg/m2] and 1368 females [age, 48.8 (10.6) years; TGs, 1.5 (0.8) mmol/L; total cholesterol, 5.8 (1.2) mmol/L; body mass index, 27.6 (5.5) kg/m2] recruited as a representative 1% population sample in 9 Czech districts according the WHO protocol (12). Additionally, 111 HTG individuals [TGs >10 mmol/L; mean (SD), 22.4 (24.1) mmol/L; age, 51.4 (9.6) years] and 8 individuals with type III hyperlipidemia [all APOE22 genotype; TGs, 6.7 (6.7) mmol/L; age, 56.2 (13.8) years]. As described before, we have found an association between increased concentrations of plasma TG and the presence of the Trp19 allele (6). The same allele was also found to be more frequent in HTG patients (8). In contrast to Schaefer et al. (1), we found no significant interaction between the APOAV Trp19 variant, APOE2, and hypertriglyceridemia: of 111 HTG patients, 4 were carriers of the APOE22 genotype and 1 of these had the APOAV Trp19 allele. Of the 13 APOE32 heterozygotes, 5 had Trp at position 19. Among the HTG patients were 39 other Trp19 carriers, and but only 5 of them had at least 1 APOE2 allele (for more details, see Table 11 ). In the population sample of 2559 individuals, we detected 20 APOE22 homozygotes, and 4 of them also had the APOAV Trp19 allele. Moreover, none of these 4 individuals had high TGs (1.37, 1.67, 2.32, and 4.52 mmol/L, respectively). Finally, of 8 APOE22 homozygotes with type III hyperlipidemia, only 3 were carriers of the APOAV Trp19 allele. On the other hand, it is noteworthy to mention that the proportion of carriers of the Trp19 allele was high among the HTG patients with APOE34 or APOE24 genotypes. In the HTG group, >50% of the patients with the Trp19 allele also had APOE42 or APOE43 genotypes, in contrast to only 13% of such individuals in the population (P <0.001; for details, see Table 11 ). The other APOAV variants (T−1131C and Val153Met) exhibit no interaction with APOE in the genetic determination of different forms of hypertriglyceridemia (details not shown). In summary, our results exclude the possibility that there is an exclusive interaction between the APOE22 genotype and APOAV Ser19>Trp variant and hypertriglyceridemia in Caucasians, as suggested in the study by Schaefer et al. (1). In contrast, we detected a strong association between hypertriglyceridemia and a combination of the genotypes APOE43 (APOE42) and APOAV +Trp19. Whether the interaction between the APOE polymorphism and the APOAV Ser19>Trp variant can lead to hypertriglyceridemia in other ethnic groups needs to be analyzed further. APOE and APOAV variants in the population sample and in the HTG patients.1 Numbers and percentages (in parentheses) of individuals in either the total analyzed groups or (in bold) just for each row so that frequency of the Ser/Trp genotype could be compared among the carriers of different APOE genotypes. Significant differences (P <0.005) between the total population and patients. APOE and APOAV variants in the population sample and in the HTG patients.1 Numbers and percentages (in parentheses) of individuals in either the total analyzed groups or (in bold) just for each row so that frequency of the Ser/Trp genotype could be compared among the carriers of different APOE genotypes. Significant differences (P <0.005) between the total population and patients. This work was supported by Grants 7600-2 and NB 7392-3 (Internal Grant Agency of Ministry of the Health of the Czech Republic), 301/02/D065 (Grant Agency of the Czech Republic), and MSM0021620807 and 1M6798582302 (Ministry of Education, Youth and Sports of the Czech Republic).