MTRR 66A&gt;G polymorphism in relation to congenital heart defects

Beynum, Ingrid M. van; Kouwenberg, M.; Kapusta, Livia; Heijer, Martin den; Linden, Ivon J. M. van der; Daniëls, Otto; Blom, Henk J.

doi:10.1515/cclm.2006.254

Cited by 35 publications

(35 citation statements)

References 36 publications

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“…In addition, the 66AG/524CT combined genotype was associated with a 1.6-fold higher risk of VSD, while the 66GG/524CT combined genotype was associated with a 2.5-fold increased risk of PDA, compared with controls. Although some previous researchers reported that the two polymorphisms (A66G and C524T) of the MTRR gene are not associated with an increased risk of CHDs (van Beynum et al, 2006;Fredriksen et al, 2007;Verkleij-Hagoort et al, 2008;Shaw et al, 2009), we found a modest association between the A66G and C524T alleles of the MTRR gene and CHDs in the Chinese Han population. These differences between reports might be due to ethnic heterogeneity.…”

Section: Discussioncontrasting

confidence: 99%

A66G and C524T polymorphisms of the methionine synthase reductase gene are associated with congenital heart defects in the Chinese Han population

Zeng¹,

Liu²,

Tong³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. Congenital heart defects (CHDs) are the most common birth defects; genes involved in homocysteine/folate metabolism may play important roles in CHDs. Methionine synthase reductase (MTRR) is one of the key regulatory enzymes involved in the metabolic pathway of homocysteine. We investigated whether two polymorphisms (A66G and C524T) of the MTRR gene are associated with CHDs. A total of 599 children with CHDs and 672 healthy children were included; the polymorphisms were detected by PCR and RFLP analysis. Significant differences in the distributions of A66G and C524T alleles were observed between CHD cases and controls, and slightly increased risks of CHD were associated with 66GG and 524CT genotypes (odds ratios = 1.545 and 1.419, respectively). The genotype frequencies of 524CT in the VSD subgroup, 66GG and 524CT in the PDA subgroup were significantly different from those of controls. In addition, the combined 66AA/524CT, 66AG/524CT and 66GG/524CT in CHDs had odds ratios = 1.589, 1.422 and 1.934, respectively. Increased risks were also observed in 66AA/524CT and 66GG/524CT for ASD, 66AG/524CT for VSD, as well as 66GG/524CT for PDA. In conclusion, MTRR A66G and C524T polymorphisms are associated with increased risk of CHDs.

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Section: Discussioncontrasting

confidence: 99%

A66G and C524T polymorphisms of the methionine synthase reductase gene are associated with congenital heart defects in the Chinese Han population

Zeng¹,

Liu²,

Tong³

et al. 2011

Genet. Mol. Res.

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“…We also demonstrated that the common MTRR c.66 AϾG variant was not associated with CHD in our study subjects, confirming previous reports. 24 These results accentuate the potentially important involvement of noncoding region variants of folate pathway core genes in the origin of CHD. However, further confirmatory studies are needed in other ethnic groups because our initial observations involved only Chinese populations.…”

Section: Discussionmentioning

confidence: 96%

Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

Zhao

Yang²,

Gong³

et al. 2012

Circulation

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Background— 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— Here, we report that the c.56+781 A>C (rs326119) variant of intron-1 of MTRR significantly increases the risk of CHD in the Han Chinese population. In 3 independent case-control studies involving a total of 2340 CHD patients and 2270 healthy control participants from different geographic areas, we observed that patients carrying the heterozygous AC and homozygous CC genotype had a 1.40-fold (odds ratio=1.40; P =2.32×10 −7 ) and 1.84-fold (odds ratio=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 polymerase chain reaction 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 CCAAT/enhancer binding protein-α binding affinity. In addition, healthy individuals with the homozygous CC genotype had significantly elevated levels of plasma homocysteine compared with 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 single-nucleotide polymorphisms in noncoding regions of the homocysteine/folate metabolism pathway core genes for their potential contributions to the origin of CHD.

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“…The only study to examine the effect of MTRR polymorphisms concluded that neither maternal nor case genotype significantly affected risk [13]. Another study found that inadequate maternal intake of vitamin B 12 was associated with increased risk for a CHD-affected child [14].…”

Section: Discussionmentioning

confidence: 99%

“…However, few clinical studies have investigated the association between MTR/MTRR/ vitamin B 12 and risk for CHD. The only study to examine the effect of MTRR polymorphisms concluded that neither maternal nor case genotype significantly affected risk [13]. However, a study found that inadequate maternal intake of vitamin B 12 , which leads to methionine synthase deficiency, was associated with increased risk for a CHD-affected child [14].…”

Section: Introductionmentioning

confidence: 99%

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Deng

Elmore

Lawrance

et al. 2008

Molecular Genetics and Metabolism

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Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for pregnancy complications and birth defects. Methionine synthase reductase (MTRR) is required for activation of methionine synthase, a folate-and vitamin B 12 -dependent enzyme. A polymorphism in MTRR (p.I22M), present in the homozygous state in 25% of many populations, may increase risk for neural tube defects. To examine the impact of MTRR deficiency on early development and congenital heart defects, we used mice harboring a gene-trapped (gt) allele in Mtrr. Female mice (Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt ) were mated with male Mtrr +/g mice. Reproductive outcomes and cardiac phenotype (presence of defects and myocardial thickness) were assessed at E14.5. Mtrrdeficient mothers had more resorptions and more delayed embryos per litter (resorptions per litter: 0.29 ± 0.13; 1.21 ± 0.41; 1.87 ± 0.38 and delayed embryos per litter: 0.07 ± 0.07; 0.14 ± 0.14; 0.60 ± 0.24 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers respectively). Placentae of Mtrr gt/gt mothers were smaller and their embryos were smaller, with myocardial hypoplasia and a higher incidence of ventricular septal defects (VSD) per litter (0; 0.57 ± 0.30; 1.57 ± 0.67 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt groups respectively). Embryonic Mtrr gt/gt genotype was associated with reduced embryonic length, reduced embryonic and placental weight, and higher incidence of VSD, but did not affect myocardial thickness or embryonic delay. We conclude that Mtrr deficiency adversely impacts reproductive outcomes and cardiac development in mice. These findings may have implications for nutritional prevention of heart defects, particularly in women with the common MTRR polymorphism.

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MTRR 66A>G polymorphism in relation to congenital heart defects

Abstract: These data indicate that maternal MTRR 66A>G polymorphism is not a risk factor for CHD. Maternal MTRR 66GG genotype with compromised vitamin B(12) status may possibly result in increased CHD risk. In addition to folate, vitamin B(12) supplementation may contribute to the prevention of CHD.

Cited by 35 publications

References 36 publications

A66G and C524T polymorphisms of the methionine synthase reductase gene are associated with congenital heart defects in the Chinese Han population

A66G and C524T polymorphisms of the methionine synthase reductase gene are associated with congenital heart defects in the Chinese Han population

Functional Variant in Methionine Synthase Reductase Intron-1 Significantly Increases the Risk of Congenital Heart Disease in the Han Chinese Population

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

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