Aging, Environment, & DiseaseDNA Methylation and Hydroxymethylation

Hypertriacylglycerolaemia: Genetic and epigenetic factors jointly regulate circulating triacylglycerol levels

hypertriacylglycerolaemia(1)Apolipoprotein A5 gene (APOA5) is one of the genes implicated in contributing to a  predisposition for hypertriacylglycerolaemia (HTG),  a complex polygenic pathology that is highly influenced by environment. Hypertriacylglycerolaemia is characterized by having high circulating triacylglycerol levels and is a significant risk factor for cardiovascular disease and atherosclerosis. This genetic predisposition has an inherited component (based on polymorphisms) as well as an acquired component regulated by the environment (epigenetic modifications). We hypothesized that the integrated analysis of both components will improve our capacity to estimate APOA5 gene contribution to HTG.

We followed a recruit-by-genotype strategy to study a population of individuals with high cardiovascular disease risk. We selected 44 carriers of at least one APOA5 SNP (-1131T>C and/or, S19W and/or 724C>G, all of them being previously associated with HTG) and compared them against 34 individuals wild-type for these SNPs. DNA methylation patterns of three APOA5 regions [promoter, exon 2 and CpG island (CGI) in exon 3] were evaluated using sodium bisulfite conversion followed by  pyrosequencing. We also obtained information of plasma biochemical analysis and lipoprotein plasma profile distribution analysed by nuclear magnetic resonance using the LipoProfile-3 algorithm.

As expected, carriers of APOA5 SNPs had an average of 57.5% higher circulating triacylglycerol (TG) levels. APOA5 promoter and exon 3 were hypermethylated whereas exon 2 was hypomethylated. Exon 3 methylation positively correlated with TG plasma level and with a proatherogenic lipoprotein profile. We found the highest TG concentrations in carriers of at least one SNP and with a methylation percentage in exon 3 ≥82%. We also generated four models in order to explain plasma TG variability: the first (composed by traditional factors as gender, body mass index and age) explained 27.8% of the variability; the second (composed by traditional factors + SNPs information) increased the prediction value by 4%; while the third model (composed by traditional factors + methylation information) increased the value by 7%. The last model, composed by the traditional, genetic and epigenetic information, increased TG prediction value by 7.5%, relative to the first model.

In conclusion, CGI methylation in exon 3 of APOA5 acts in combination with -1131T>C, S19W and 724C>G polymorphisms in the individual’s predisposition to high circulating levels. This serves as an example that combined analysis of SNPs and methylation applied to a larger set of genes would improve our understanding of predisposition to HTG as well as other diseases.

 

Original Article:

Oliva, I., Guardiola, M., Vallve, J., Ibarretxe, D., Plana, N., Masana, L., Monk, D., & Ribalta, J. (2016). APOA5 genetic and epigenetic variability jointly regulate circulating triacylglycerol levels Clinical Science, 130 (22), 2053-2059 DOI: 10.1042/CS20160433

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Iris Oliva Rodriguez

Iris Oliva Rodriguez

  • Clarence A. ‘Sonny’ Williams

    Isn’t the conclusion a given for all diseases? That is, either a methylation, histone modification, or methylation + histone modification pattern (of some sort) is always necessary for the expression of all genes, including SNPs correlated with a disease. Therefore, the exciting news about this specific research is finding the likely SNP/methylation pattern that is necessary for HTG. In so finding the location and methylation pattern, interventions might be possible, which interventions could eliminate the methylation pattern necessary for the SNP’s expression.

    • Iris Oliva

      First of all, thank you for your comment. Well, in our case, lipid-related diseases have a genetic component and a enviromental component. For that, we added DNA methylation to the study, because methylation is a key epigenetic gene expression regulator highly influenced by enviroment (diet, smoking, excercise…). We selected APOA5 as a key gene in triglycerides metabolism and we demonstrated that both, snps and methylation information jointly increase hypertriglyceridemia variability explanation. Of course, this aproach is valid for other gene studies related to other diseases.

      • Clarence A. ‘Sonny’ Williams

        Thanks. I’m trying to understand the sequence of events in order to determine what “DNA methylation regulates” means. Your paper brought it to my attention that I may be misunderstanding how epigenetic mechanisms work.

        Environmental factors/signals like diet, smoking, etc. activate internal signaling pathways, which eventually activate transcription factor complexes (TFs). These TF complexes are DNA-sequence specific; that is, they don’t bind to “just any old DNA region.” TFs then bind specific DNA regions, thus converting the environmental signal into a biological response that is very specific as to the gene whose expression will be modified. After being bound by TFs, other proteins or complexes are attracted to the TF-bound region. In the case of methylation, that would be DNMT1. The 5th carbon on cytosine is thus methylation, which then attracts chromatin modifying factors like CTCF. Those chromatin modifying factors then physically conform the chromatin so that the TF-bound region is brought into the proximity of either an enhancer or silencer, thereby finally altering the TF-bound gene’s expression pattern.

        Thus, arguing that DNA methylation (or other epigenetic mechanism) has a “regulatory function” is misleading. They are followers of TF-initiated responses to the environmental factor. I think the distinction is important, as it discredits any thoughts that the environmental signal is unrelated to evolved DNA sequences. That is, no environmental signal alters gene expression patterns unless a “receptive” DNA sequence has been inherited.

        Is there are a problem of my understanding? Do you agree that ascribing a regulatory function to DNA methylation can be misleading?