Abstract
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.
Highlights
Neural tube defects (NTDs) are congenital anomalies of the brain and spinal cord that cause significant morbidity and mortality (Sutton et al, 2008)
We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the Dihydrofolate reductase (DHFR) 19 bp deletion, Methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) 1958G>A, Methylene tetrahydrofolate reductase (MTHFR) 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G
The evidence for genetic factors lies in the increased recurrence risk in siblings of individuals with NTDs, the increased risk for NTDs among other relatives, and the increased risk for birth defects overall among both close and distant relatives (MRC Vitamin Study Research Group, 1991; Deak et al, 2008)
Summary
Neural tube defects (NTDs) are congenital anomalies of the brain and spinal cord that cause significant morbidity and mortality (Sutton et al, 2008). Ireland has had high rates of NTDs (Coffey, 1983), with rates decreasing significantly in the last 50 years (Botto et al, 2006). Both environmental and genetic factors have been implicated in the etiology of NTDs. The evidence for environmental factors lies in the protective effect of periconceptional folic acid intake (Czeizel and Dudas, 1992). The evidence for genetic factors lies in the increased recurrence risk in siblings of individuals with NTDs, the increased risk for NTDs among other relatives, and the increased risk for birth defects overall among both close and distant relatives (MRC Vitamin Study Research Group, 1991; Deak et al, 2008). Maternal relatives have higher NTD and overall birth defect rates than paternal relatives, consistent with a combination of genetic and epigenetic mechanisms contributing to NTD and overall birth defects risk (Byrne et al, 1996; Byrne, 2008, 2010, 2011; Deak et al, 2008)
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