AUTHOR=Babić Božović Ivana , Stanković Aleksandra , Živković Maja , Vraneković Jadranka , Mahulja-Stamenković Vesna , Brajenović-Milić Bojana 

TITLE=Maternal LINE-1 DNA Methylation and Congenital Heart Defects in Down Syndrome

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00041

DOI=10.3389/fgene.2019.00041

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Down syndrome (DS) is one of the most common chromosomal abnormalities associated with congenital heart defects (CHD), with approximately 40 to 60% of cases showing cardiac defects. This study assessed (i) the association between maternal LINE-1 methylation and the occurrence of CHDs in children with DS and (ii) the impact of endogenous maternal factors (<italic>MTHFR</italic> C677T polymorphism and maternal age) and exogenous maternal factors (cigarette smoking, alcohol intake, medication use, body mass index and dietary habits such as folate intake) on maternal LINE-1 methylation and on the occurrence of CHD in children with DS.</p><p><bold>Patients and Methods:</bold> The study included 90 mothers of children with DS of maternal origin (49% DS-CHD<sup>+</sup> mothers/51% DS-CHD<sup>−</sup> mothers). LINE-1 DNA methylation was analyzed in peripheral blood lymphocytes by quantification of LINE-1 methylation using the MethyLight method. <italic>MTHFR</italic> C677T polymorphism genotyping was performed using PCR-RFLP.</p><p><bold>Results:</bold> LINE-1 methylation was not significantly different between DS-CHD<sup>+</sup> and DS-CHD<sup>−</sup> mothers (<italic>P</italic> = 0.997). Combination of <italic>MTHFR</italic> C677T genotype/diet and BMI were significant independent predictors of LINE-1 DNA methylation in DS-CHD<sup>+</sup> mothers (β −0.40, <italic>P</italic> = 0.01 and β −0.32, <italic>P</italic> = 0.03, respectively). In the analyzed multivariate model (model <italic>P</italic> = 0.028), these two factors explained around 72% of the variance in LINE-1 DNA methylation in mothers of children with DS and CHD. The group with the highest BMI (≥30 kg/m2) had significantly lower LINE-1 methylation than the group with normal BMI (Bonferroni <italic>post hoc P</italic> = 0.03) and the overweight group (Bonferroni <italic>post hoc P</italic> = 0.04). The lowest LINE-1 DNA methylation values were found in DS-CHD<sup>+</sup> mothers with the CT+TT genotype and a low-folate diet; the values were significantly lower than the values in mothers with the CC genotype and a folate-rich diet (Bonferroni <italic>post hoc P</italic> = 0.04).</p><p><bold>Conclusion:</bold> Association between maternal LINE-1 methylation and CHD in children with DS was not found. Study showed that the <italic>MTHFR</italic> genotype/diet combination and BMI were significantly associated with LINE-1 methylation in mothers of children with DS-CHD<sup>+</sup>. These results highlight the need for a multifactorial approach to assess the roles of endogenous and exogenous maternal factors in maternal LINE-1 DNA methylation and the consequent pathologies in children. More extensive studies in a larger sample may help elucidate these relationships.</p>