The C677T mutation of the 5,10-methylenetetrahydrofolate reductase gene is a moderate risk factor for spina bifida in Italy.

Franchis, R. de; Buoninconti, Anna; Mandato, Claudia; Pepe, Alessia; Sperandeo, Maria Pia; Gado, Roberto Del; Capra, Valeria; Salvaggio, E; Andria, Generoso; Mastroiacovo, P

doi:10.1136/jmg.35.12.1009

Cited by 62 publications

(46 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Since the A1298C mutation influences enzyme activity and homocysteine and folate concentrations to a lesser extent than does the C677T mutation, it may be expected that the A1298C mutation is a risk factor for NTD, but with a smaller relative risk. On the contrary, we found that the A1298C polymorphism is an important risk factor for the Italian population with a risk associated with the 1298C/C genotype that is even higher than that reported for the homozygous mutant genotype of the C677T mutation (de Franchis et al 1998). MTHFR nucleotide 1298 is located on the regulatory domain of the protein, where it may be involved in protein stabilization (Shan et al 1999).…”

Section: Discussioncontrasting

confidence: 46%

See 1 more Smart Citation

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population

et al. 2002

View full text Add to dashboard Cite

Section: Discussioncontrasting

confidence: 46%

“…The C677T mutation was studied in the Italian population, which has a relatively low prevalence of NTDs. In this study, an increased NTD risk was found for the T/T genotype (odds ratio [OR] ϭ 1.73), and the corresponding attributable fraction was 10.8% (de Franchis et al 1998). …”

Section: Abstract Neural Tube Defects ·mentioning

confidence: 86%

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population

et al. 2002

View full text Add to dashboard Cite

“…These proportions were similar between subjects born in the North and in the South. Genotype frequencies were similar in the two sets of controls (newborns and adults) 17 ; therefore, we pooled the sets.…”

Section: Resultsmentioning

confidence: 99%

“…The subjects with spina bifida had been included in another study of MTHFR allelic variants. 17 Of the 203 children with spina bifida, 173 (85%) had myelomeningocele and 30 (15%) had lipomeningocele. All affected children were enrolled from three spina bifida centers in three cities (Genova, Roma, Napoli) with the assistance of the Italian Federation of Spina Bifida and the Hydrocephalus Association.…”

Section: Study Populationmentioning

confidence: 99%

Spina bifida and folate-related genes: A study of gene-gene interactions

Franchis¹,

Botto

Sebastio³

et al. 2002

Genetics in Medicine

View full text Add to dashboard Cite

Purpose: To assess whether interactions of common alleles of two folate genes contribute to spina bifida risk.Methods: Case-control study, comparing 203 children with spina bifida to 583 controls. Results: Homozygosity for the 677C-T allele of 5,10-methylenetetrahydrofolate reductase (MTHFR) alone was associated with an odds ratio for spina bifida of 1.57 (95% confidence interval [CI], 1.02-2.38). For the 844ins68 allele of cystathionine-␤-synthase alone, the odds ratio was 0.83 (95% CI, 0.39 -1.64). For the joint genotype, the odds ratio was 3.69 (95% Spina bifida is a common and severe congenital anomaly that yearly affects approximately 1 in 1,000 newborns in Italy 1 and 200,000 newborns or more worldwide. 2,3 Clinical and epidemiologic evidence, such as the variability of occurrence rates by geography, time, socioeconomic status, and ethnicity, and the relatively low recurrence risk within families, suggests that the etiology of spina bifida involves interactions between multiple genetic and environmental factors. 4,5 However, defining these factors and interactions has proven difficult. The protective effect of folic acid on the occurrence of spina bifida 6 -8 suggests that the study of folate metabolism might identify some of the genetic determinants of spina bifida. Several candidate genes have been studied, including 5,10-methylenetetrahydrofolate reductase (MTHFR), cystathionine-␤-synthase (CBS), methionine synthase, and methionine synthase reductase. A pooled analysis suggests that homozygosity for the 677C-T allele of MTHFR in infants is associated with approximately a 70% increased risk for spina bifida. 9 Common mutations of other genes, such as the 844ins68 allele of CBS, 10 have also been described, although their association with spina bifida is still unclear. Limited data are available on potential interactions among alleles of different folate-related genes. In 1997, Ramsbottom and associates 11 from Ireland reported data on the 677C-T allele of MTHFR and the 844ins68 allele of CBS and suggested that they indicated no interaction effects for spina bifida. We suggested that these data were consistent with the presence of interaction, 12 although the original authors thought otherwise. 13 Subsequent studies yielded discordant findings, with one study from Germany reporting no interaction effects 14 and another study from the United States reporting possible evidence for interaction. 15 In this report, which expands findings reported in abstract, 16 we assess the independent and joint effects of these two common alleles (677C-T and 844ins84) on the risk for spina bifida, using data from a large case-control study from Italy. MATERIALS AND METHODS Study populationThe study population comprised 203 children with open spina bifida without other unrelated major malformations (case-subjects) and 583 healthy young adults and newborns (control-subjects). The subjects with spina bifida had been included in another study of MTHFR allelic variants. 17 Of the 203 children with spina bifida, 173 (85%) had my...

show abstract

“…Studies from Europe also report that the C677T mutation does not result in a significant risk factor for NTD either independently or in association with other polymorphic alleles involved in folate metabolism. [36][37][38] Moreover, we are the first to present data on MTHFR C677T/A1298C haploid genotypes in combination with RFC-1 A80G variant. Examination of combined genotypes revealed that haplotypes 677CT/1298CC and 677TT/ 1298CC were not observed in our NTD families and controls.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

View full text Add to dashboard Cite

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.

show abstract

The C677T mutation of the 5,10-methylenetetrahydrofolate reductase gene is a moderate risk factor for spina bifida in Italy.

Cited by 62 publications

References 5 publications

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population

Spina bifida and folate-related genes: A study of gene-gene interactions

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

Contact Info

Product

Resources

About