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European Heart Journal Advance Access originally published online on March 7, 2006
European Heart Journal 2006 27(8):981-987; doi:10.1093/eurheartj/ehi815
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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Maternal MTHFR 677C>T is a risk factor for congenital heart defects: effect modification by periconceptional folate supplementation

Ingrid M. van Beynum1,*, Livia Kapusta1, Martin den Heijer2,3, Sita H.H.M. Vermeulen2, Margreet Kouwenberg4, Otto Daniëls1 and Henk J. Blom5

1Children's Heart Centre, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
2Department of Endocrinology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
3Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
4Department of Pediatrics, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
5Laboratory of Pediatrics and Neurology, Radboud University Medical Centre, 6500 HB Nijmegen, The Netherlands

Received 19 July 2005; revised 10 December 2005; accepted 9 February 2006; online publish-ahead-of-print 7 March 2006.

* Corresponding author. Tel: +31 24 3614427; fax: +31 24 3619052. E-mail address: i.vanbeynum{at}cukz.umcn.nl

Aims Periconceptional folate supplementation prevents neural tube defects and possibly congenital heart defects (CHD) as well. The search for candidate genes involved in the folate metabolism includes the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism. We studied the association between MTHFR 677C>T variants and CHD risk. The interaction with periconceptional folate supplementation was also investigated.

Methods and results A case–control study and a family-based transmission disequilibrium test (TDT) were conducted to explore this association. In 133 triads, the TDT revealed no association of the fetal 677T allele with the development of a heart defect. In 158 mothers with a CHD-affected child, the maternal MTHFR 677CT and TT genotypes in combination with no use of periconceptional folate supplements were associated with, respectively, a three-fold (OR 3.3 95% CI 1.46–7.32) and six-fold (OR 6.3 95% CI 2.32–17.27) increased risk for conotruncal heart defects in offspring. In a case-only study, the interaction between periconceptional folate supplementation and maternal MTHFR genotype was significant (P=0.012).

Conclusion The maternal MTHFR 677C>T variants are a risk factor for CHD in offspring, confined to conotruncal heart defects. A gene-environment interaction between maternal MTFHR 677CT and TT genotypes with periconceptional folate supplementation was observed. These findings provide a mechanism of the protective role of folate and support the thesis that periconceptional folate supplementation might prevent CHD.

Key Words: Congenital heart defects • Folate • MTHFR • Periconceptional folate supplementation


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