Congenital heart defects and biomarkers of methylation in children: a case-control study

P>Background Derangements in the maternal methylation pathway, expressed by global hypomethylation and hyperhomocysteinemia, are associated with the risk of having a child with a congenital heart defect (CHD). It is not known whether periconception exposure to these metabolic derangements contributes to chromosome segregation and metabolic programming of this pathway in the foetus. Design In a Dutch population-based case-control study of 143 children with CHD and 186 healthy children, we investigated S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total homocysteine (tHcy), the vitamins folate and B12 and the functional single nucleotide polymorphisms in the folate gene MTHFR 677C > T and 1298A > C. Comparisons were made between cases and controls adjusting for age, medication, vitamin use and CHD family history. Results In the overall CHD group, the median concentrations of SAM (P = 0 center dot 011), folate in serum (P = 0 center dot 021) and RBC (P = 0 center dot 030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0 center dot 001), SAH (P = 0 center dot 012) and serum folate (P = 0 center dot 010) independent of carriership of MTHFR polymorphisms. Highest concentrations of SAM, SAH and folate RBC were observed in complex syndromic CHD. The subgroup of children with Down syndrome, however, showed significantly higher SAH (P = 0 center dot 037) and significantly lower SAM:SAH ratio (P = 0 center dot 034) compared with other complex CHD, suggesting a state of global hypomethylation. Conclusion High concentrations of methylation biomarkers in very young children are associated with complex CHD. Down syndrome and CHD may be associated with a global hypomethylation status, which has to be confirmed in tissues and global DNA methylation in future studies.