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Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene
  1. C A Hobbs,
  2. S J James,
  3. A Parsian,
  4. P A Krakowiak,
  5. S Jernigan,
  6. J J Greenhaw,
  7. Y Lu,
  8. M A Cleves
  1. Department of Pediatrics, Birth Defects Research Section, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas, USA
  1. Correspondence to:
 Dr Charlotte A Hobbs
 University of Arkansas for Medical Sciences, College of Medicine, Department of Pediatrics, 11219 Financial Centre Parkway, Suite 250, Little Rock, AR 72211, USA; hobbscharlotte{at}; reprints will not be available


Background: Most non-syndromic congenital heart defects (CHD) are caused by a complex interaction between maternal lifestyle factors, environmental exposures, and maternal and fetal genetic variants. Maternal periconceptional intake of folic acid containing vitamin supplements is reported to decrease the risk of CHD. The 677C→T and 1298A→C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene decrease enzyme activity.

Objective: To examine the relation between CHD and maternal and fetal MTHFR polymorphisms

Methods: 375 nuclear families were studied. The transmission/disequilibrium test was used to test for transmission distortion in complete triads. A log-linear approach was used to test for associations between CHD and maternal and offspring polymorphisms, and to estimate independently the contributions of maternal and fetal variants to relative risks. Haplotype frequencies were estimated and a haplotype transmission disequilibrium test carried out.

Results: The 1298C allele was transmitted less often than expected (p = 0.0013). There was no distortion in the transmission of the 677T allele, neither was there evidence of a parent of origin effect in the transmission of either of the single nucleotide polymorphisms. The 677C–1298C haplotype was also transmitted less often than expected (p = 0.0020). The relative risk associated with inheriting one copy of the 1298C allele was 0.64 (95% confidence interval, 0.48 to 0.87) and the that associated with inheriting two copies of the 1298C allele, 0.38 (0.21 to 0.70).

Conclusions: The apparent protective effect of the MTHFR 1298C allele against CHD could have several explanations and further study is needed.

  • CHD, congenital heart defect
  • LD, linkage disequilibrium
  • MTHFR, methylenetetrahydrofolate reductase
  • NBDPS, National Birth Defects Prevention Study
  • SNP, single nucleotide polymorphism
  • TDT, transmission disequilibrium test
  • congenital heart defect
  • polymorphism
  • folic acid

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  • This study was supported by grants from the National Institute of Child Health and Human Development No 5R01 HD39054-05, National Center for Research Resources No 1C06 RR16517-01 and 3C06 RR16517-01S1, and Cooperative Agreement No U50/CCU613236-08 from the Centers for Disease Control and Prevention (CDC). Funding was also provided by the Arkansas Biosciences Institute (ABI); a partnership of scientists from Arkansas Children’s Hospital; Arkansas State University; the University of Arkansas Division of Agriculture; the University of Arkansas, Fayetteville; and the University of Arkansas for Medical Sciences. The contents of this letter to JMG are solely the responsibility of the authors and do not necessarily represent the official views of the CDC, National Institutes of Health, or ABI.

  • Conflicts of interest: none declared