Congenital heart defects and biomarkers of methylation in children: A case-control study
Eur J Clin Invest 2011; 41 (2): 143-150Background 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 = 0.011), folate in serum (P = 0.021) and RBC (P = 0.030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0.001), SAH (P = 0.012) and serum folate (P = 0.010) 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 = 0.037) and significantly lower SAM:SAH ratio (P = 0.034) 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.
|Keywords||Aetiology, Congenital heart malformations, Epigenetics, Fallot tetralogy, Folate, Homocysteine, Methylation, adolescent, adult, aorta coarctation, aorta valve stenosis, article, child, concentration (parameters), congenital heart malformation, controlled study, cyanocobalamin, female, folic acid, genotype, heart atrium septum defect, heart ventricle septum defect, homocysteine, human, hypoplastic left heart syndrome, major clinical study, male, methylation, priority journal, pulmonary valve stenosis, s adenosylhomocysteine, s adenosylmethionine, school child, single nucleotide polymorphism, vitamin|
|Persistent URL||dx.doi.org/10.1111/j.1365-2362.2010.02388.x, hdl.handle.net/1765/23552|
Obermann-Borst, S.A., van Driel, L.M.J.W., Helbing, W.A., de Jonge, R., Wildhagen, M.F., Steegers, E.A.P., & Steegers-Theunissen, R.P.M.. (2011). Congenital heart defects and biomarkers of methylation in children: A case-control study. European Journal of Clinical Investigation, 41(2), 143–150. doi:10.1111/j.1365-2362.2010.02388.x