Department of Obstetrics and Gynaecology/Division of Obstetrics and Prenatal Medicine, Erasmus MC, University Medical Centre, Rotterdam, the Netherlands.
Eur J Clin Invest. 2011 Feb;41(2):143-50. doi: 10.1111/j.1365-2362.2010.02388.x. Epub 2010 Sep 27.
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.
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.
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.
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.
母体甲基化途径的紊乱，表现为整体低甲基化和高同型半胱氨酸血症，与患有先天性心脏病（CHD）的儿童的风险相关。目前尚不清楚围孕期暴露于这些代谢紊乱是否会导致胎儿中该途径的染色体分离和代谢编程。
在一项针对 143 名患有 CHD 的儿童和 186 名健康儿童的荷兰基于人群的病例对照研究中，我们研究了 S-腺苷甲硫氨酸（SAM）、S-腺苷同型半胱氨酸（SAH）、总同型半胱氨酸（tHcy）、叶酸和维生素 B12 以及叶酸基因 MTHFR 677C>T 和 1298A>C 的功能单核苷酸多态性。通过比较病例和对照组，调整年龄、药物、维生素使用和 CHD 家族史。
在整个 CHD 组中，SAM（P=0.011）、血清（P=0.021）和 RBC（P=0.030）中的叶酸浓度中位数显著高于对照组。亚组分析表明，这主要归因于复杂 CHD，SAM（P<0.001）、SAH（P=0.012）和血清叶酸（P=0.010）水平较高，与 MTHFR 多态性无关。在复杂综合征性 CHD 中观察到最高浓度的 SAM、SAH 和 RBC 叶酸。然而，与其他复杂 CHD 相比，唐氏综合征患儿的 SAH 显著升高（P=0.037），SAM:SAH 比值显著降低（P=0.034），表明存在整体低甲基化状态，这需要在未来的组织和全基因组 DNA 甲基化研究中得到证实。
非常年幼的儿童中甲基化生物标志物的高浓度与复杂 CHD 相关。唐氏综合征和 CHD 可能与整体低甲基化状态有关，这需要在未来的研究中在组织和全基因组 DNA 甲基化中得到证实。
