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J Med Genet. 2006 Feb;43(2):162-6. Epub 2005 Jun 10.

Congenital heart defects and genetic variants in the methylenetetrahydroflate reductase gene.



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.


To examine the relation between CHD and maternal and fetal MTHFR polymorphisms.


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.


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).


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

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