Methylenetetrahydrofolate reductase C677T and reduced folate carrier 80 G>A polymorphisms are associated with an increased risk of conotruncal heart defects

Background: Folic acid has an important role during embryologic development, particularly the development of the cardiovascular system. Methods: We analyzed the involvement of eight polymorphisms in genes related to folic-acid metabolism, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (MTHFD1), transcobalamin (TCN2), reduced folate carrier (RFC), nicotinamide-N-methyltransferase (NNMT) and natriuretic peptide precursor A (NPPA) as risk factors of conotruncal heart defects. Results: In single-locus analyses, the genotype frequencies of MTHFR rs1801133 C>T were 18.4% (CC), 50.4% (CT), and 31.1% (TT) in the subjects with conotruncal heart defects and 31.6% (CC), 52.9% (CT), and 15.4% (TT) in control subjects, and the difference was significant (p=0.001). Logistic regression analyses revealed that, if the MTHFR rs1801133 CC homozygote genotype was used as the reference group, subjects carrying the TT variant homozygote had a significant 3.46-fold [odds ratio (OR) 3.46; 95% confidence interval (CI) 1.83-6.55] increased risk of conotruncal heart defects. If the RFC rs1051266 GG homozygote genotype was used as the reference group, subjects carrying the GA variant heterozygote had a significant 1.68-fold (OR 1.68; 95% CI 1.02-2.78) increased risk of conotruncal heart defects. In stratification analyses, the MTHFR rs1801133 C>T genotype was associated with an increased risk for tetralogy of Fallot (TOF) and transposition of great artery (TGA) in homozygote comparisons, the dominant genetic model, and the recessive genetic model. The RFC rs1051266 GA genotype was associated with an increased risk for TGA. compared with wild-type homozygotes and, in the dominant genetic model, the RFC rs1051266 GA/AA genotype was also associated with a significantly increased risk of TGA compared with RFC rs1051266 GG genotypes. Conclusions: These data suggest that genotypes for the MTHFR C677T and RFC rs1051266 polymorphism might be associated with the risk of conotruncal heart defects.