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Maternal Folate-Related Gene Environment Interactions and Congenital Heart Defects

Hobbs, Charlotte A. MD, PhD; Cleves, Mario A. PhD; Karim, Mohammad A. MD, PhD; Zhao, Weizhi MS; MacLeod, Stewart L. PhD

doi: 10.1097/AOG.0b013e3181e80979
Original Research

OBJECTIVE: To investigate whether women with congenital heart defect (CHD)–affected pregnancies were more likely to have functional single-nucleotide polymorphisms in genes encoding enzymes in folate-dependent pathways.

METHODS: A population-based case–control study of 572 women with CHD-affected pregnancies and 363 women in the control group was conducted. DNA samples were genotyped for single-nucleotide polymorphisms in three genes encoding for folate pathway enzymes. Maternal lifestyle factor information was obtained using standardized interviews.

RESULTS: Women in the case group were 1.5 times more likely to be obese (body mass index of 30 or higher) compared with those in the control group. Obese women carrying the MTHFR TT genotype were 4.6 times more likely to have an affected pregnancy compared with normal-weight women carrying a CC genotype. Obese women carrying one or two copies of the A allele in the BHMT polymorphism were 1.8 times more likely to have a CHD-affected pregnancy than were normal-weight women carrying a BHMT GG genotype. Among women who smoked, those carrying a TCII CG or GG genotype were 1.8 times more likely to have an affected fetus than were women who smoked and carried a CC genotype. Among women who drank alcohol, those carrying a TCII CG or GG genotype were 1.7 times more likely to have an affected fetus than were women who drank and carried a CC genotype.

CONCLUSION: Results indicate that functional polymorphisms in folate-related genes increase the risk of having a fetus with CHD when maternal lifestyle factors that alter folate metabolism are present.


Maternal folate-related genetic polymorphisms interact with lifestyle factors to increase the risk of fetal congenital heart defects.

From the University of Arkansas for Medical Sciences, College of Medicine, Department of Pediatrics, Birth Defects Research Section, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas.

The National Birth Defects Prevention Study is supported by the Centers for Disease Control and Prevention (Cooperative Agreement No. U50/CCU613236-10). Also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD039054-07) and the Arkansas Biosciences Institute (the major research component of the Tobacco Settlement Proceeds Act of 2000).

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or the National Institutes of Health.

Corresponding author: Charlotte A. Hobbs, Arkansas Center for Birth Defects Research and Prevention, 13 Children's Way, Slot 512-40, Little Rock, AR 72202; email:

Financial Disclosure All authors received support for travel to meetings for the study or otherwise that was provided by the funding sources of this article.

© 2010 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.