Abstract
BackgroundMethylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and play an important role in maintaining genomic stability and gene expression. To derive insight into the association between genome-wide methylation status and tetralogy of fallot (TOF), we compared the methylation status of LINE-1 element between TOF patients and controls. The methylation of the NKX 2–5, HAND 1, and TBX 20 promoter regions was also evaluated.MethodsGenomic DNA from right ventricular tissue samples was obtained from 32 patients with TOF and 15 control subjects. Sequenom MassARRAY platform was performed to examine the methylation levels of LINE-1, NKX2-5, HAND1 and TBX20. Mann–Whitney U test was used to compare differences in methylation levels between two groups.ResultsThe methylation level of LINE-1 was significantly lower in patients with TOF, with a median of 57.95% (interquartile range [IQR]: 56.10%–60.04%), as opposed to 59.70% in controls (IQR: 59.00%–61.30%; P = 0.0021). The highest LINE-1 methylation level was 61.3%. The risk of TOF increased in subjects with the lowest methylation levels (less than or equal to 59.0%; OR = 14.7, 95% CI: 1.8–117.7, P = 0.014) and in those with medium methylation levels (59.0%–61.3%; OR = 2.0, 95% CI: 0.3–14.2, P = 0.65). An ROC curve analysis showed a relatively high accuracy of using the LINE-1 methylation level in predicting the presence of TOF (AUC = 0.78, 95% CI: 0.65–0.91; P = 0.002). The association of the LINE-1 methylation level with TOF was only observed in males (P = 0.006) and not in females (P = 0.25). Neither age nor gender was found to be associated with the LINE-1 methylation level in patients or controls. Higher methylation levels of NKX2-5 and HAND1 and lower methylation levels of TBX20 were also observed in patients with TOF than in controls. No association was found between the methylation levels of NKX2-5, HAND1 and TBX 20 with the LINE-1 methylation level.ConclusionsLower LINE-1 methylation levels are associated with increased risk of TOF and may provide important clues for the development of TOF.
Highlights
Methylation levels of long interspersed nucleotide elements (LINE-1) are representative of genomewide methylation status and play an important role in maintaining genomic stability and gene expression
The methylation level of Long interspersed nucleotide element-1 (LINE-1) was significantly lower in patients with tetralogy of fallot (TOF), with a median value of 57.95%, as opposed to 59.70% (IQR: 59.00%–61.30%) in controls (P = 0.0021, Figure 2A)
Subjects in the lowest quartile had a greater risk of TOF than those in the highest quartile (OR = 14.7, 95% confidence intervals (95% CI): 1.8–117.7, Figure 4 (A) Correlation between LINE-1 methylation level and age in the control group (n = 15) and in the TOF patients (n = 32)
Summary
Methylation levels of long interspersed nucleotide elements (LINE-1) are representative of genomewide methylation status and play an important role in maintaining genomic stability and gene expression. TOF accounts for 10% of all congenital heart defects, with an incidence of 3.6 per 10,000 live births [2] It is biological insights into this set of developmental diseases have been gained only recently, and their exact etiology remains unknown [5]. NKX25 and HAND1 are known to act as regulatory genes during cardiac development They are evolutionarily inflexible in their regulation of the differentiation of cardiac muscle cells and morphogenesis of the heart [7,8]. The cancer genome is frequently characterized by hypermethylation of specific genes concurrently with an overall decrease in the level of 5′ methyl cytosine. This hypomethylation of the global genome promotes chromosomal instability, translocation, gene disruption, and reactivation of endoparasitic sequences [17]
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