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Licensed Unlicensed Requires Authentication Published by De Gruyter September 21, 2011

MTRR 66A>G polymorphism in relation to congenital heart defects

  • Ingrid M. van Beynum , Margreet Kouwenberg , Livia Kapusta , Martin den Heijer , Ivon J.M. van der Linden , Otto Daniels and Henk J. Blom


Background: Evidence is accumulating that periconceptional folic acid supplementation may prevent congenital heart defects (CHD). The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in the folate- and vitamin B12-dependent remethylation of homocysteine to methionine. We studied the influence of the MTRR 66A>G polymorphism on CHD risk. In addition, possible interaction between this variant and plasma methylmalonic acid (MMA) concentrations, as an indicator of intracellular vitamin B12 status, was investigated.

Methods: Case-control and case-parental studies were conducted to explore this association. In total, 169 CHD patients and 213 child controls, and 159 mothers with a CHD-affected child and 245 female controls were included.

Results: The maternal MTRR 66AG and GG vs. AA genotypes revealed an odds ratio (OR) of 1.3 (95% CI 0.72–2.20) and 1.3 (0.71–2.37), respectively. Family-based transmission disequilibrium analysis did not reveal a significant association of the foetal 66G allele with the development of a heart defect in children (χ2=2.94, p=0.086). Maternal 66GG genotype in combination with high MMA concentration (above the 80th percentile) was associated with a three-fold (OR 3.3, 95% CI 0.86–12.50) increased risk for all types of CHD in offspring.

Conclusions: These data indicate that maternal MTRR 66A>G polymorphism is not a risk factor for CHD. Maternal MTRR 66GG genotype with compromised vitamin B12 status may possibly result in increased CHD risk. In addition to folate, vitamin B12 supplementation may contribute to the prevention of CHD.

Clin Chem Lab Med 2006;44:1317–23.

Corresponding author: I.M. van Beynum, Children's Heart Centre, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands Phone: +31-24-3614427, Fax: +31-24-3619052,


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Received: 2006-7-19
Accepted: 2006-9-10
Published Online: 2011-9-21
Published in Print: 2006-11-1

©2006 by Walter de Gruyter Berlin New York

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