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Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.

ABSTRACT: There is currently considerable interest in the relationship between variation in genes that are involved in the folate-homocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step transmission/disequilibrium test. Analysis of data on variants of two genes involved in homocysteine remethylation/methionine biosynthesis--methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G--provided evidence that both variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. For both variants, the risk of having a child with spina bifida appears to increase with the number of high-risk alleles in the maternal genotype: MTR (R1=2.16, 95% CI 0.92-5.06; R2=6.58, 95% CI 0.87-49.67) and MTRR (R1=2.05, 95% CI 1.05-3.99; R2=3.15, 95% CI 0.92-10.85). These findings highlight the importance of considering both the maternal and embryonic genotype when evaluating putative spina bifida susceptibility loci.

SUBMITTER: Doolin MT

PROVIDER: S-EPMC385102 | biostudies-literature | 2002 Nov

REPOSITORIES: biostudies-literature

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Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.

Doolin Marie-Therese MT Barbaux Sandrine S McDonnell Maeve M Hoess Katy K Whitehead Alexander S AS Mitchell Laura E LE

American journal of human genetics 20021009 5

There is currently considerable interest in the relationship between variation in genes that are involved in the folate-homocysteine metabolic axis and the risk of spina bifida. The evaluation of this relationship is, however, complicated by the potential involvement of both the maternal and the embryonic genotype in determination of disease risk. The present study was designed to address questions regarding both maternal and embryonic genetic risk factors for spina bifida by use of the two-step ...[more]

PMID: 12375236

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Project description:Background The vitamin A derivative, retinoic acid (RA), is a potent teratogenic agent that induces a variety of congenital abnormalities including neural tube defects. The embryopathology of RA has been extensively investigated and retinol receptors play important roles during organogenesis, development and neural tube closure. Still, the mechanisms by which RA influences these processes are not completely understood. Methods We used a custom-made mouse genome 32K oligonucleotide microarray to determine the gene expression profiles of mouse embryo spinal cord samples that had been exposed to vehicle or RA. Then, we performed a GSEA (gene set enrichment analysis) on the gene expression data by searching MSigDB (v2.5) c2 gene sets (canonical pathways) and c5 gene sets (curated GO terms), with set size restraints on the range to avoid over-narrow or over-broad categories. Results Using microarray technology, the present study identifies 85 genes in the spinal cord that exhibit at least a 1.5-fold change between control samples and samples with spina bifida aperta. A gene set enrichment analysis showed that maternal exposure to RA induced spinal bifida that were associated with altered expression of genes involved in pro- or anti-apoptosis, cell proliferation, migration, cytoskeleton components, and cell or focal adhesion, indicating that defective functions of these cell components and biological processes preceded the abnormal development of neural tube. Conclusions Maternal exposure to RA induced spinal bifida that were associated with altered expression of genes involved in pro- or anti-apoptosis, cell proliferation, migration, cytoskeleton components, and cell or focal adhesion. As shown in previous reports, defective functions of these cell components and biological processes preceded the abnormal development of the neural tube. Our study will help the understanding of the etiology and pathology of spinal bifida. However, it should be noted that the changes in gene expression induced by RA exposure may not be an effect on events other than neural tube closure; further study is required to fully understand the molecular mechanisms and consequence of neural tube defects in embryos exposed to RA. Our study provides a global analysis of gene expression patterns in spina bifida and will help the understanding of the etiology and pathology of neural tube defects.

Dataset Information

Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.

Publications

Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida.

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