Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor

Molloy, Anne M.; Mills, James L.; Kirke, Peadar N.; Ramsbottom, Dorothy; McPartlin, Joseph; Burke, Helen; Conley, Mary; Whitehead, Alexander S.; Weir, Donald G.; Scott, John M.

doi:10.1002/(sici)1096-8628(19980630)78:2<155::aid-ajmg11>3.0.co;2-m

Cited by 75 publications

(36 citation statements)

References 21 publications

(39 reference statements)

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“…Two previous reports establishing that homocysteine and folate status of the mother has an impact on NTD outcome have highlighted the need to verify whether the maternal genotype has a direct effect on NTD risk. 39,40 In fact, it is plausible that maternal genotype could play a particular pathogenic role in NTDs, either by limiting the supply of folate to the embryo or by facilitating the accumulation and increased transfer to the embryo of homocysteine, high concentrations of which can disrupt neural tube closure in experimental models. Unfortunately, owing to sparse data, we are unable to estimate potential NTD risk among mothers carrying four mutations in genes involved in folate-related pathways.…”

Section: Discussionmentioning

confidence: 99%

Reduced folate carrier polymorphism (80A→G) and neural tube defects

et al. 2003

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Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A-G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case-control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR ¼ 2.35; 95% CI 1.21-4.58) and mothers (OR ¼ 2.74; 95% CI 0.92-8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A-C and RFC-1 80A-G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A-G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruplemutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases ¼ 11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.

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Section: Discussionmentioning

confidence: 99%

Reduced folate carrier polymorphism (80A→G) and neural tube defects

et al. 2003

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“…The thermolabile MTHFR 677C fi T (A222V) variant is a risk factor for neural tube defects (NTDs) in some but not all populations (Botto and Yang 2000) and is associated with low folate and elevated homocysteine levels. However, the MTHFR 677TT genotype accounts for only 11.4% of the population attributable fraction in Ireland (Shields et al 1999) and only partly explains low blood folates in NTD pregnancies (Molloy et al 1998). This has led to the search for additional polymorphisms which influence folate and/or homocysteine levels in relation to neural tube defects, cardiovascular disease and cancer.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the MTHFR 1298A→C and 677C→T polymorphisms as risk factors for neural tube defects

et al. 2003

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The thermolabile variant (677TT) of methylenetetrahydrofolate reductase (MTHFR) is a known risk factor for neural tube defects (NTDs). The relationship between a second MTHFR polymorphism (1298A fi C) and NTD risk has been inconsistent between studies. We genotyped 276 complete NTD triads (mother, father and child affected with an NTD) and 256 controls for MTHFR 1298A fi C. Our findings do not support a role for the 1298A fi C polymorphism in NTDs (OR 0.85 (95% CI 0.49-1.47), p= 0.55), nor do we observe a combined effect with the 677C fi T polymorphism.

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“…It has been reported that low vitamin B12 concentrations could lead to reduced methylation of homocysteine to methionine, enhancing the impairment of folate metabolism and increasing the risk for development of NTDs (van der Put and Blom, 2000). It has also been reported that the combination of MTHFR polymorphisms and low folate and vitamin B12 intake is associated with a greater risk for NTDs than each variable alone, indicating a strong genetic-nutritional interaction (Molloy et al, 1998;Stegmann et al, 1999). Cunha et al (2002) reported that the mutant C allele was not associated with differences in folate and vitamin B12 concentrations in children with NTDs.…”

Section: Discussionmentioning

confidence: 99%

Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group

Yildiz¹,

Erdoğan²,

Solak³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The etiology underlying neural tube defects (NTDs) is not fully understood and is believed to involve a complex milieu of genetic and environmental factors. The A1298C polymorphism in the methylenetetrahydropholate reductase gene (MTHFR) has been associated with mild risk for NTDs. In this study, the genotype distribution of the MTHFR gene A1298C polymorphism and the levels of serum homocysteine, vitamin B12, and folate were evaluated in 33 children with NTDs, their mothers, and 46 healthy controls. Genotyping of the A1298C polymorphism was performed by real-time polymerase chain reaction. The A and C allele frequencies in children with NTDs and their mothers were similar to controls (P = 0.160). The 1298AA and 1298CC genotype frequencies (P = 0.551 and 0.062, respectively) in children with NTDs and their mothers did not differ from controls. On the other hand, the 1298AC genotype frequencies in children with NTDs and their mothers were significantly different from controls (P = 0.025). The genotype frequency of 1298AC was lower in children with NTDs than in controls. There was no significant association between clinical distribution of NTDs and 1298AA/AC/CC genotypes (P > 0.05). Serum vitamin B12 levels were higher in children with NTDs than their mothers and controls (P = 0.001). There were no differences among serum homocysteine and folate levels in all groups (P = 0.494 and 0.141, respectively). Both genetic and nutritional factors are important in the etiology of NTDs. Thus, the A1298C polymorphism cannot be regarded as a major risk factor for NTDs.

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Low blood folates in NTD pregnancies are only partly explained by thermolabile 5,10-methylenetetrahydrofolate reductase: Low folate status alone may be the critical factor

Cited by 75 publications

References 21 publications

Reduced folate carrier polymorphism (80A→G) and neural tube defects

Reduced folate carrier polymorphism (80A→G) and neural tube defects

Analysis of the MTHFR 1298A→C and 677C→T polymorphisms as risk factors for neural tube defects

Lack of association between the methylenetetrahydropholate reductase gene A1298C polymorphism and neural tube defects in a Turkish study group

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