DNA Polymorphisms of the Apolipoprotein AI/CIII/ AIV Gene Cluster Influence Plasma Cholesterol and Triglyceride Levels in the Mayans of the Yucat&amp;aacute;n Peninsula, Mexico

Ahn, Youngwook; Valdéz, Rodolfo; Reddy, A. Pramod; Cole, Shelley A.; Weiss, Kenneth M.; Ferrel, Robert E.

doi:10.1159/000154014

Cited by 27 publications

(16 citation statements)

References 6 publications

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“…In APOC3, two rare alleles in the promoter region (−482C →T and −455T →C) and a minor allele in the 3′UTR (SstI polymorphism, 3238G →C) have repeatedly been associated with elevated plasma triglyceride concentrations in several human populations [5][6][7][8][9][10][11][12][13][14][15]. However, the lack of strong functional data at least for the SstI polymorphism raises questions whether the association seen in humans is due to these sequence variants in APOC3 directly or due to other functional variants in APOC3 or possibly in one of the neighboring apolipoprotein genes.…”

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Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11

et al. 2004

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Members of the apolipoprotein gene cluster (APOA1/C3/A4/A5) on human chromosome 11q23 play an important role in lipid metabolism. Polymorphisms in both APOA5 and APOC3 are strongly associated with plasma triglyceride concentrations. The close genomic locations of these two genes as well as their functional similarity have hindered efforts to define whether each gene independently influences human triglyceride concentrations. In this study, we examined the linkage disequilibrium and haplotype structure of 49 SNPs in a 150-kb region spanning the gene cluster. We identified a total of five common APOA5 haplotypes with a frequency of greater than 8% in samples of northern European origin. The APOA5 haplotype block did not extend past the 7 SNPs in the gene and was separated from the other apolipoprotein gene in the cluster by a region of significantly increased recombination. Furthermore, one previously identified triglyceride risk haplotype of APOA5 (APOA5*3) showed no association with three APOC3 SNPs previously associated with triglyceride concentrations, in contrast to the other risk haplotype (APOA5*2), which was associated with all three minor APOC3 SNP alleles. These results highlight the complex genetic relationship between APOA5 and APOC3 and support the notion that APOA5 represents an independent risk gene affecting plasma triglyceride concentrations in humans. KeywordsSingle nucleotide polymorphism; Apolipoprotein A5; Haplotype; Linkage disequilibrium; Recombination; Four-gamete testThe apolipoprotein gene cluster on human chromosome 11q23 contains four apolipoprotein genes (APOA1/C3/A4/A5) in a genomic interval of approximately 60 kb [1]. Three of these genes (APOA1/C3/A4) have been well described, and each plays an important role in lipid metabolism in humans and mice. For example, mice lacking apoA1 have significantly reduced plasma high-density lipoprotein (HDL) cholesterol levels [2]. In contrast, mice lacking apoC3 show lower concentration of plasma triglycerides compared to control littermates [3].In humans, analyses of genetic sequence variants around these three genes have revealed polymorphisms associated with plasma lipid levels (for a review, see [4] in APOA1 primarily affect HDL-cholesterol cocentrations, while variation in APOC3 is primarily associated with altered plasma triglyceride concentrations. In APOC3, two rare alleles in the promoter region (−482C →T and −455T →C) and a minor allele in the 3′UTR (SstI polymorphism, 3238G →C) have repeatedly been associated with elevated plasma triglyceride concentrations in several human populations [5][6][7][8][9][10][11][12][13][14][15]. However, the lack of strong functional data at least for the SstI polymorphism raises questions whether the association seen in humans is due to these sequence variants in APOC3 directly or due to other functional variants in APOC3 or possibly in one of the neighboring apolipoprotein genes.Recently, we identified a fourth member (APOA5) of the chromosome 11 apolipoprotein gene cluster, located approximatel...

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Haplotype analysis of the apolipoprotein gene cluster on human chromosome 11

et al. 2004

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“…Genetic studies have demonstrated a key role for apoCIII in determining plasma triglyceride levels in humans. A sequence polymorphism in the 3Ј-untranslated region of the apoCIII gene has been associated with elevated triglyceride levels in several populations (5)(6)(7)(8)(9). In addition, clinical studies have reported that some hypertriglyceridemic patients have elevated apoCIII levels and increased apoCIII production rates (10 -12).…”

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Mitogen-activated Protein Kinase Regulates Transcription of the ApoCIII Gene

Reddy¹,

Yang²,

Taylor³

et al. 1999

Journal of Biological Chemistry

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The transcriptional regulation of the apoCIII gene by hormonal and metabolic signals plays a significant role in determining plasma triglyceride levels. In the current work we demonstrate that the apoCIII gene is regulated by the mitogen-activated protein (MAP) kinase signaling pathway. In HepG2 cells, repression of MAP kinase activity by treatment with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD98059 caused a 5-8-fold increase in apoCIII transcriptional activity. Activation of MAP kinase by phorbol ester treatment caused a 3-5-fold reduction in apoCIII transcription. The region of the apoCIII promoter responsible for this regulation was mapped in transiently transfected HepG2 cells to a 6-base pair element located at ؊740. The major protein binding to this site was identified as the nuclear hormone receptor HNF4. An increase in HNF4 mRNA and protein levels was observed in HepG2 cells after treatment with PD98059, indicating that the MAP kinase pathway regulates the expression of the HNF4 gene. These findings demonstrate that the apoCIII gene can be regulated by signals acting through the MAP kinase pathway and that this regulation is mediated, at least in part, by changes in the amount of HNF4.ApoCIII is a component of very low density lipoprotein and functions as a key regulator of serum triglyceride levels (1). In transgenic animals, overexpression of the apoCIII gene caused hypertriglyceridemia (2), with as little as 30 -40% excess apo-CIII causing a 2-fold increase in triglyceride levels (3). Likewise, mice that did not express apoCIII because of a gene knockout had abnormally low circulating triglyceride levels (4). Genetic studies have demonstrated a key role for apoCIII in determining plasma triglyceride levels in humans. A sequence polymorphism in the 3Ј-untranslated region of the apoCIII gene has been associated with elevated triglyceride levels in several populations (5-9). In addition, clinical studies have reported that some hypertriglyceridemic patients have elevated apoCIII levels and increased apoCIII production rates (10 -12). ApoCIII modulates serum triglyceride metabolism by reducing both lipolysis and uptake of triglyceride-rich lipoproteins (3, 13-16).The apoCIII gene is transcriptionally regulated by a variety of metabolic and hormonal signals. In a previous study, we demonstrated that in a hypoinsulinemic animal model of diabetes, hepatic apoCIII transcriptional activity is regulated by insulin and that these changes correlated with changes in plasma triglyceride levels (17). Further evidence that apoCIII transcriptional activity plays a significant role in determining plasma triglyceride levels comes from the analysis of a genetic polymorphism in the human apoCIII promoter region. Two major sequence variants of the apoCIII promoter can be found in the human population. The most common (wild-type) allele differs from the less common (variant) allele by five single base pair DNA sequence differences. A haplotype of the apoCIII locus contain...

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“…The most extensively studied one is the SstI polymorphism located in the 3'UTR of the gene (20). Associations of the minor allele S2 with higher levels of TG (21)(22)(23)(24)(25)(26) and lower levels of HDL-C (27) have been reported in various ethnic groups. However, the interactions of this genetic variant with a high-CHO diet on the ratios of serum lipids and apolipoproteins have not been reported before.…”

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confidence: 99%

“…The SstI polymorphism is formed by a transversion from C to G and is located in the 3' untranslated region (3'UTR) of this gene (20). A number of studies have reported that the S2 carriers of the APOC3 SstI polymorphism had higher plasma levels of TG (21)(22)(23)(24)(25)(26), TC (27,28), LDL-C (27), and lower levels of HDL-C (27). The S2 allele was also associated with elevated plasma concentrations of apoCIII (29,30) and apoB (27,29,30), but not with lower apoAI levels (29).…”

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“…Previous studies have shown that both the high-CHO diet and the APOC3 SstI polymorphism affect the serum lipid and lipoprotein profiles (11,12,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Therefore, we supposed that the different genotypes of the APOC3 SstI polymorphism may have different responses to the high-CHO diet regarding the ratios of serum lipids and apolipoproteins.…”

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