Polymorphisms in genes related to folate and cobalamin metabolism and the associations with complex birth defects

R. Brouns, N. Ursem, J. Lindemans, W. Hop, S. Pluijm, E. Steegers, R. Steegers-Theunissen

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)


Objective: To investigate the associations between biomarkers and genetic variants involved in homocysteine metabolism and the risk of complex birth defects. Methods: Total homocysteine (tHcy), folate, cobalamin, apo-transcobalamin (apo-TC) and apo-haptocorrin (apo-HC) were measured in the amniotic fluid of 82 women who were pregnant with a child having a complex birth defect, such as neural tube defect, cleft lip and/or palate, heart defect or omphalocele, and in 110 women pregnant with a non-malformed child. The determined genotypes of the child comprised of 5, 10-methylenetetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G) and transcobalamin (TCN2 776C>G). Univariate and multivariate logistic regression analyses were performed. Results: Significantly lower cobalamin and higher apo-TC, apo-HC, tHcy and folate concentrations were determined in amniotic fluids of cases compared with controls (p ≤ 0.001). Logistic regression analysis revealed that after adjustment for maternal age, children carrying the MTHFR 677T allele showed a four-fold increased risk of having a complex birth defect, OR (95% CI) = 4.0 (1.1-15.4). Other genotypes did not show significant associations. Conclusion: The MTHFR 677C>T polymorphism in conjunction with reduced folate- and/or cobalamin status may increase the risk of complex birth defects.

Original languageEnglish
Pages (from-to)485-493
Number of pages9
JournalPrenatal Diagnosis
Issue number6
Publication statusPublished - Jun 2008
Externally publishedYes


  • Amniotic fluid
  • Folic acid
  • Homocysteine
  • Malformations
  • Vitamin B12


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