Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women

Barbosa, Patricia R.; Stabler, Sally P.; Machado, Amanda Luiz; Braga, Rodolpho C.; Hirata, Rosário Dominguez Crespo; Hirata, Mário Hiroyuki; Sampaio-Neto, Luiz F.; Allen, Robert H.; Guerra-Shinohara, Elvira María

doi:10.1038/sj.ejcn.1602810

Cited by 81 publications

(68 citation statements)

References 45 publications

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“…It has been reported that although the common MTRR c.66 AϾG (p.I22M) missense mutation is not significantly associated with CHD in children, the homozygotes mutant G allele is associated with elevated plasma homocysteine concentrations in pregnant women. 20 However, to date, no studies of the possible correlation between variations in the noncoding region of MTRR and CHD have been published. In the present study, we have investigated polymorphisms in the noncoding region of the MTRR gene in 3 independent case-control studies with 2340 CHD cases and 2270 controls from the Han Chinese population.…”

Section: Clinical Perspective On P 490mentioning

confidence: 99%

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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Section: Clinical Perspective On P 490mentioning

confidence: 99%

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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“…Using gene-specific primers, DNA was PCR-amplified and restriction digested with specific enzymes, and examined for RFLPs of MTHFR (C677T & A1298C), CBS (844ins68 bp), MTR (A2756G) and RFC1 (G80A) (Chango et al, 2000;Dutta et al, 2005;Rai et al, 2006;Barbosa et al, 2008). The SNPs and the 68 bp insertion of CBS were resolved, respectively, on 3.5 and 2% agarose gels.…”

Section: Genetic Analysismentioning

confidence: 99%

Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population

Sukla

Raman

2011

Eur J Clin Nutr

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Background/Objectives: Unlike most Western populations, MTHFR 677T is a rare allele and a risk factor for a variety of disorders in India. What kind of nutritional (environmental) and/or genetic factors could contribute to the genetic risk is not known. To assess the incidence of hyperhomocysteinemia and its correlation with the polymorphism in homocysteine (Hcy)-pathway genes and associated cofactors in the native populations of eastern India. Subjects/Methods: Healthy population from four eastern states of India. Genotyping of SNPs, HPLC and chemiluminescencebased assay for homocysteine, vitamin B12 and folic acid.Results: Approximately 30% of the population has hyperhomocysteinemia (415 mmol/lit; hypHcy) with varying frequencies in the four states from where samples were collected (n ¼ 1426). Polymorphisms of MTR and CBS do not affect hypHcy. 677T and 1298C alleles of MTHFR and G80 RFC-1 show association with hypHcy. In contrast, RFC-1 80AA is protective even in presence of 677T MTHFR. Addition of each mutant allele has an additive effect on Hcy level. Vitamin B12 (cofactor in methionine synthesis) clearly modulates the genotypic effect on Hcy level. Although frequency of individuals with low folic acid is B11, 49% of the population is vitamin B12 deficient (o220 pg/lit) and has a significant negative correlation with Hcy. Individuals with optimum vitamin B12 and folic acid generally have low Hcy, even in risk genotypes. Conclusions: One of the plausible reasons for susceptibility of individuals with MTHFR C677T in the studied population to various disorders is the high frequency of hyperhomocysteinemia and vitamin B12 deficiency in the 'healthy population'. Apparently, supplementation of vitamin B 12 to this health-impoverished community may help lessen the risk of several multifactorial disorders.

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“…Conflicting results of the studies on the relationship between the 1298A>C polymorphism and AIS, both in children and adults, can be found [12][13][14][15][16][17]. Previously, it was observed that the MTHFR 1298A>C polymorphism in combined analysis with the 677C>T polymorphism increased homocysteine levels as well as lowered plasma folate levels [18]. However, some studies do not confirm such a relationship [19].…”

Section: Introductionmentioning

confidence: 99%

Is the 1298A>C polymorphism in the MTHFR gene a risk factor for arterial ischaemic stroke in children? The results of meta-analysis

2018

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An elevated level of homocysteine is a risk factor for vascular diseases, brain atrophy and several other disorders. The 1298A>C polymorphism (rs1801131) leads to mildly decreased MTHFR activity. Previously, it was observed that the MTHFR 1298A>C polymorphism in combined analysis with the MTHFR 677C>T polymorphism increases homocysteine levels. However, conflicting results on its relation to ischaemic stroke in children can be found. We conducted a meta-analysis to analyse possible connections between the MTHFR 1298A>C polymorphism and ischaemic stroke in paediatric patients. We identified available data published before December 2016 using appropriate keywords and searching PubMed as well as the references cited in the found articles. Eight case-control studies were included in the meta-analysis (426 children with stroke and 778 controls). Statistical analyses were made using R and Comprehensive Meta-Analysis softwares to investigate the impact of polymorphism in four models: dominant, recessive, additive and allelic. No publication bias was observed in the meta-analysis. We demonstrated no relationship between the 1298A>C polymorphism and ischaemic stroke in children in the case of recessive, additive and allelic models. However, the results of the dominant model analysis should be treated with caution due to the sensitivity analysis results. After omitting one of the included study, we observed a significant association between the carriers of the MTHFR C allele (cases with AC + CC genotypes) and ischaemic stroke in children (OR 1.35 95% CI 1.02-1.79, p = 0.035 in a fixed effects model). In conclusion, the 1298A>C polymorphism in the MTHFR gene is not a risk factor for ischaemic stroke in paediatric patients.

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Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women

Abstract: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

Cited by 81 publications

References 45 publications

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

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

Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population

Is the 1298A>C polymorphism in the MTHFR gene a risk factor for arterial ischaemic stroke in children? The results of meta-analysis

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