| Summary: | <p>Abstract</p> <p>Background</p> <p>Methylation 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 <it>NKX</it> 2<it>–</it>5, <it>HAND</it> 1, and <it>TBX</it> 20 promoter regions was also evaluated.</p> <p>Methods</p> <p>Genomic 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, <it>NKX</it>2-5, <it>HAND</it>1 and <it>TBX</it>20. Mann–Whitney U test was used to compare differences in methylation levels between two groups.</p> <p>Results</p> <p>The 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%; <it>P</it> = 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, <it>P</it> = 0.014) and in those with medium methylation levels (59.0%–61.3%; OR = 2.0, 95% CI: 0.3–14.2, <it>P</it> = 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; <it>P</it> = 0.002). The association of the LINE-1 methylation level with TOF was only observed in males (<it>P</it> = 0.006) and not in females (<it>P</it> = 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 <it>NKX</it>2-5 and <it>HAND</it>1 and lower methylation levels of <it>TBX</it>20 were also observed in patients with TOF than in controls. No association was found between the methylation levels of <it>NKX</it>2-5, <it>HAND</it>1 and <it>TBX</it> 20 with the LINE-1 methylation level.</p> <p>Conclusions</p> <p>Lower LINE-1 methylation levels are associated with increased risk of TOF and may provide important clues for the development of TOF.</p>
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