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Risk of congenital heart defects is influenced by genetic variation in folate metabolism

Published online by Cambridge University Press:  05 April 2012

Karen E. Christensen ,
Yassamin Feroz Zada ,
Charles V. Rohlicek ,
Gregor U. Andelfinger ,
Jacques L. Michaud ,
Jean-Luc Bigras ,
Andrea Richter ,
Marie-Pierre Dubé  and
Rima Rozen
Karen E. Christensen
Affiliation:
Departments of Pediatrics and Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
Yassamin Feroz Zada
Affiliation:
Institut de Cardiologie de Montréal/StatGen, Montreal, Quebec, Canada
Charles V. Rohlicek
Affiliation:
Division of Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Gregor U. Andelfinger
Affiliation:
Department of Pediatrics, Cardiovascular Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada Service of Pediatric Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Jacques L. Michaud
Affiliation:
Division of Medical Genetics, Research Center of CHU Sainte Justine, University of Montréal, Montreal, Quebec, Canada
Jean-Luc Bigras
Affiliation:
Service of Pediatric Cardiology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
Andrea Richter
Affiliation:
Division of Medical Genetics, Research Center of CHU Sainte Justine, University of Montréal, Montreal, Quebec, Canada
Marie-Pierre Dubé
Affiliation:
Institut de Cardiologie de Montréal/StatGen, Montreal, Quebec, Canada
Rima Rozen*
Affiliation:
Departments of Pediatrics and Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada
*
Correspondence to: Dr Rima Rozen, PhD, FRSC, FCAHS, FCCMG, McGill University-Montreal Children's Hospital Research Institute, 4060 Ste Catherine West, Room 200, Montreal, Quebec, Canada H3Z 2Z3. Tel: +514 412 4358; Fax: +514 412 4331; E-mail: rima.rozen@mcgill.ca
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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.

Keywords

Ventricular septal defectgenetic polymorphismone-carbon folate metabolismmethylenetetrahydrofolate reductasemethionine synthase reductase
Type
Original Article
Information
Cardiology in the Young , Volume 23 , Issue 1 , February 2013 , pp. 89 - 98
Copyright
Copyright © Cambridge University Press 2012

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