Carter Consulting, Inc. and Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention Atlanta, GA, USA.
Front Genet. 2013 Nov 6;4:223. doi: 10.3389/fgene.2013.00223. eCollection 2013.
Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative ("risk genotypes") and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.
围孕期叶酸的使用通常可以预防神经管缺陷（NTDs）。母亲和儿童中参与叶酸代谢的基因变体与 NTD 的发生有关。我们鉴定了患有神经管缺陷的爱尔兰家族。在这些家族中，我们观察到神经管缺陷和出生缺陷总体上在母系中比在父系中发生的频率更高。本研究的目的是寻找遗传效应的证据，以解释这些出生缺陷在母系与父系中发生的差异。我们对通过参加脊柱裂协会而确定的 322 名受 NTD 影响的爱尔兰家族的血液样本进行了基因分型。我们寻找了五个遗传多态性在母系与父系中的分布差异：DHFR 19 bp 缺失、MTHFD1 1958G>A、MTHFR 1298A>C、MTHFR 677C>T 和 SLC19A1 80A>G。除了单独研究基因型外，我们还确定了每个亲属（“风险基因型”）中与降低叶酸代谢相关的基因型数量，并比较了这些基因型在母系与父系亲属中的分布。总的来说，母系亲属中与降低叶酸代谢相关的基因型数量高于父系亲属（p=0.017）。我们预计亲属会与 NTD 患者及其母亲具有相同的风险基因型。然而，我们观察到母系亲属具有更多的任何风险基因型，而不是特定的基因型。观察到的遗传效应表明存在一种表观遗传机制，其中降低的叶酸代谢导致与 NTD 及母系中所见其他出生缺陷增加相关的表观遗传改变。未来对 NTD 和其他出生缺陷病因的研究可能受益于包括多代扩展家族，以探索潜在的表观遗传机制。
