title: Risk of congenital heart defects is influenced by genetic variation in folate metabolism.
abstract: Genetic disturbances in folate metabolism may increase risk for congenital heart defects. We examined the association of heart defects with four polymorphisms in folate-related genes (methylenetetrahydrofolate reductase (MTHFR) c.677C.T, MTHFR c.1298A.C, methionine synthase reductase (MTRR) c.66A.G, and reduced folate carrier (SLC19A1) c.80A.G) in a case-control study of children (156 patients, 69 controls) and mothers of children with heart defects (181 patients, 65 controls), born before folic acid fortification. MTRR c.66A.G in children modified odds ratios for overall heart defects, specifically ventricular septal defect and aortic valve stenosis (p-value below 0.05). The 66GG and AG genotypes were associated with decreased odds ratios for heart defects (0.42, 95% confidence interval (0.18-0.97) and 0.39 (0.18-0.84), respectively). This overall association was driven by decreased risk for ventricular septal defect for 66GG and AG (odds ratio 0.32 (0.11-0.91) and 0.25 (0.09-0.65)) and decreased odds ratio for aortic valve stenosis for 66AG (0.27 (0.09-0.79)). The association of ventricular septal defect and 66AG remained significant after correction for multiple testing (p = 0.0044, multiple testing threshold p = 0.0125). Maternal MTHFR 1298AC genotype was associated with increased odds ratio for aortic valve stenosis (2.90 (1.22-6.86), p = 0.0157), but this association did not meet the higher multiple testing threshold. No association between MTHFR c.677C.T or SLC19A1 c.80A.G and heart defect risk was found. The influence of folate-related polymorphisms may be specific to certain types of heart defects; larger cohorts of mothers and children with distinct sub-classes are required to adequately address risk.
authors.affiliation: Department of Pediatrics and Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Christensen
authors.forename: Yassamin Feroz
authors.initials: YF
authors.lastname: Zada
authors.forename: Charles V
authors.initials: CV
authors.lastname: Rohlicek
authors.forename: Gregor U
authors.initials: GU
authors.lastname: Andelfinger
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Bigras
authors.forename: Andrea
authors.initials: A
authors.lastname: Richter
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
mesh_terms: D001024:Aortic Valve Stenosis / Q000151:congenital / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005492:Folic Acid / Q000378:metabolism*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics*; D006345:Heart Septal Defects, Ventricular / Q000235:genetics; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D058978:Reduced Folate Carrier Protein / Q000235:genetics*
chemical_list: D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)