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


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).


CONCLUSIONS
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.
van Beynum
Ingrid M
IM
Children's Heart Centre, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. i.vanbeynum@cukz.umcn.nl
Kapusta
Livia
L
den Heijer
Martin
M
Vermeulen
Sita H H M
SH
Kouwenberg
Margreet
M
Daniëls
Otto
O
Blom
Henk J
HJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D005494:Folic Acid Deficiency / Q000178:diet therapy; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000517:prevention & control; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D016742:Preconception Care / Q000379:methods; D012307:Risk Factors
D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)