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SoBT Researchers Publish New Findings on Link Between Folic Acid Metabolism and Human Development

Neural tube defects (NTDs) are one of the most common birth defects. Affecting 1.04 per 1,000 births each year, this category of disease relates to conditions that initiate in the first month of pregnancy, and ultimately impacts upon the brain, spine, or spinal cord during development. Supplementation with folic acid; a type of B vitamin, in the diet is recognised as a preventative measure against most NTD-associated conditions such as spina bifida, greatly reducing the prevalence of NTDs, yet the metabolic and genomic mechanisms underlying these effects are not clear. As such, researchers continue to investigate the pathways and variations pertaining to folate metabolism, with the Molecular Genetics Laboratory based in the School of Biotechnology recently publishing an interesting finding on one enzyme involved in folate metabolism.

‘Folate metabolism is an essential biochemical pathway involved in important cellular processes such as DNA replication and repair’, describes Prof. Anne Parle-McDermott, senior author of the recently published research letter in the American Journal of Medical Genetics.

‘In recent years, the enzymes that are involved in this important pathway have been found to have different isoforms, with evidence suggesting variations in the genes responsible for folate metabolism may correlate with increased risk of NTDs'.

‘Our research group has been interested in a family of enzymes known as dihydrofolate reductase (DHFR). This enzyme is an important one, as it ensures that folate is in a form that can be used by the cell for making new DNA. It does this by  reducing dihydrofolate into tetrahydrofolate.

‘We have recently focused on another family member; DHFR2, which is present in humans but is absent in many animals. It’s discovery within the human genome is thought to be a product of evolution, yet the actual function of this gene is currently unknown’.

‘Apart from birth defects, DHFR is an established drug target for cancer therapy and so investigation into what role DHFR2 plays in this context is warranted. In this study, in collaboration with the National Human Genome Research Institute at the National Institute of Health (US), we performed an association study to determine whether variations in the DHFR2 gene in parents, was associated with increased risk of NTDs’.

‘To this end, we examined data from 595 trio families from Ireland that included an affected case and one or both parents, and compared this to a control population of 1000 women attending their first prenatal visit. We found there was indeed an increased risk of NTD in those who presented with particular variants of the DHFR2 gene. Common variants in genes, such as single nucleotide polymorphisms or SNPs, are a feature of all of our genes and can sometimes have subtle affects in how a given gene works in one person compared to another. This can mean increasing or decreasing one’s risk of a disease or a birth defect such as an NTD. We observed an increase in NTD risk for specific SNPs in our Irish cohort.

‘We then utilised a UK cohort to see whether this finding had a similarly significant impact. In a similar sampling strategy to that used when analysing an Irish population, 354 cases plus their parents, were recruited and two of the SNPs demonstrated to change significantly were tested in these. Interestingly, the SNPs which we associated with NTD in the Irish cohort did not correlate with NTD in the UK population’.

‘While we were able to rule out certain SNPs associated with NTD as potential quantitative biomarkers of such, the DHFR2 gene itself cannot be ruled out as having an influence on NTD etiology’.

‘Further research is required towards understanding the genetic contribution of this gene towards NTD, and further examination of the genetic variations stemming from said gene is warranted’.

For more information, the article can be accessed here.