-Homocysteine is known to be an independent risk factor for congenital heart disease (CHD). Methionine synthase reductase (MTRR) is essential for the adequate remethylation of homocysteine, which is the dominant pathway for homocysteine removal during early embryonic development. Methods and Results -Herein, we report that the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the CHD risk in the Han Chinese population. In three independent case-control studies

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... a total of 2,340 CHD patients and 2,270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (OR=1.40, P=2.32×10 -7 ) and 1.84-fold (OR=1.84, P=2.3×10 -11 ) increased risk, respectively, of developing CHD than those carrying the wild-type AA genotype. Both in vivo quantitative real-time PCR analysis of MTRR mRNA in cardiac tissue samples from CHD patients and in vitro luciferase assays in transfected cells demonstrated that the c.56+781 C allele profoundly decreased MTRR transcription. Further analysis demonstrated that the c.56+781 C allele manifested reduced CEBP binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared to the wild-type AA carriers. Conclusions -We have demonstrated that the MTRR c.56+781 A>C variant is an important genetic marker for increased CHD risk because this variant results in functionally reduced MTRR expression at the transcriptional level. Our results accentuate the significance of functional SNPs in non-coding regions of the homocysteine/folate metabolism pathway core genes for their potential contributions to the etiology of CHD.