👤 Edward A Ruiz-Narváez

The APOA5 gene, located in the APOA1/C3/A4/A5 gene cluster, is a key regulator of triglyceride metabolism. ApoAV plasma concentration is much lower as compared to other apolipoproteins such as apoCIII and apoAI. This is due in part to the fact that the APOC3-enhancer, which up-regulates transcription of the APOA1, APOC3, and APOA4 genes, does not increase expression of the APOA5 gene. We postulated that intervening Alu repeats in the APOA5-APOA4 intergenic region gene might be blocking action of the APOC3-enhancer over the APOA5-promoter. To search for evidence of functional significance of the intervening Alu sequences, we estimated nucleotide substitution rates of 21 pairs of Alu elements in the APOA5-APOA4 intergenic region by comparing published sequences of human and chimpanzee. Also, we scanned the intergenic region for the presence of binding sites of the insulator protein CTCF. Seven out of the nine found CTCF binding sites were located in the first half of the intergenic region. Five out of those seven CTCF binding sites were placed inside Alu elements. Based on their substitution rates, we found two clearly defined groups of Alu sequences: a slow-evolving group (mean 0.98 +/- 0.18) and a fast-evolving group (mean 2.74 +/- 0.54). Alu repeats with lower substitution rate tended to be located up to 14-kb upstream of the APOA5 gene, to belong to the oldest J-family and to have an opposite orientation to the APOA5 gene. Some Alu sequences may have functional relevance on the regulation of the APOA5-gene expression. Show less

Plasma apolipoprotein (apo) C-III strongly predicts myocardial infarction (MI) and directly activates atherogenic processes in vascular cells. Genetic variation in the insulin response element of the APOC3 promoter is associated with an increased risk of MI. The objective was to determine whether the APOC3 promoter variation affects plasma apo C-III concentrations and MI only when insulin sensitivity is normal. The APOC3*222 haplotype, defined by the minor alleles of the single nucleotide polymorphisms 3238C-->G, -455T-->C, and -482C-->T, was studied in 1703 matched nonfatal case-control pairs with MI in the Central Valley of Costa Rica. We used fasting hyperglycemia and abdominal obesity as surrogates for insulin sensitivity. The APOC3*222 haplotype was associated with higher apo C-III concentrations only in those with the lowest waist circumference or fasting glucose concentration. The association between the APOC3*222 haplotype and nonfatal MI, previously reported in this population, was strongly influenced by fasting hyperglycemia and abdominal obesity. The odds ratios for MI for the APOC3*222 haplotype were 1.72 (95% CI: 1.16, 2.54) and 1.84 (1.31, 2.59) in subjects in the lowest quintiles of abdominal obesity and fasting hyperglycemia, respectively, and were 0.75 (0.54, 1.05) and 1.16 (0.85, 1.59) in subjects in the highest quintiles, respectively (P for interaction <0.05). The results support the concept that mutations in the APOC3 promoter inhibit the down-regulation of APOC3 expression by insulin. This cardioprotective system becomes dysfunctional in abdominal obesity and hyperglycemia. Show less

Genetic variation in the APOC3 and APOA5 genes has been associated with plasma triglyceride concentrations and may affect the risk of myocardial infarction (MI). To assess whether APOC3/A5 haplotypes are associated with risk of MI, we examined three single-nucleotide polymorphisms (SNPs) in APOC3 (3238C>G, -455T>C, and -482C>T) and six SNPs in the APOA5 gene (-1131T>C, c.-3A>G, c.56C>G, IVS3+476G>A, c.553G>T, and c.1259T>C) in incident cases (n = 1,703) of a first nonfatal MI matched for gender, age, and area of residence with population-based controls (n = 1,703). Conditional logistic regression models, adjusted for potential environmental confounders, were used for analysis. The common APOC3*222 haplotype was more frequent in cases than in controls (17.4% and 13.7%, respectively, P < 0.001) and was associated with increased risk of MI [odds ratio (OR) = 1.27; 95% confidence interval (95% CI), 1.09, 1.48] compared with APOC3*111 wild-type haplotype. This association was independent of the APOA5 SNPs. Although the APOC3 3238G, APOA5 -1131C, APOA5 c.-3G, and APOA5 c.1259C alleles were associated with higher triglyceride plasma concentrations, these effects could not explain the associations with MI in this population. In summary, this study supports the hypothesis that haplotypes in the APOC3 gene but not in the APOA5 gene increase susceptibility to MI. Show less