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

Parle‐McDermott, Anne; Mills, James L.; Kirke, Peadar N.; O’Leary, Valerie B.; Swanson, Deborah A.; Pangilinan, Faith; Conley, Mary; Molloy, Anne M.; Cox, Christopher; Scott, John M.; Brody, Lawrence C.

doi:10.1007/s10038-003-0008-4

Cited by 58 publications

(56 citation statements)

References 19 publications

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“…However, this linkage disequilibrium is not complete, since the presence of some individuals with the haplotype T-C was observed in some studies (Shi et al, 2003;Parle-McDermott et al, 2003;Scala et al, 2006). In our study, in a total sample of 266 women, only one with this haplotype was observed, confirming its negative selection.…”

Section: Discussionsupporting

confidence: 59%

Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil

Biselli

Goloni-Bertollo²,

Zampieri

et al. 2008

Genet. Mol. Res.

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ABstRACt. The aim of the present study was to investigate the effect of polymorphisms C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, A2756G in methionine synthase reductase (MTR) gene and A80G in reduced folate carrier 1 (RFC1) gene, and plasma homocysteine (Hcy), on the maternal risk for Down syndrome (DS). Seventy-two DS mothers and 194 mothers who had no children with DS were evaluated. The investigation of the MTHFR C677T, MTR A2756G and RFC1 A80G polymorphisms was performed by polymerase chain reaction and enzyme digestion and the MTHFR A1298C polymorphism by allele-specific polymerase chain reaction. Hcy quantification was carried out by liquid chromatography-tandem mass spectrometry. The median number of polymorphic alleles for the four loci tested was greater in DS mothers compared to the control group, and the presence of three or more polymorphic alleles increased the risk for having a child with DS 1.74 times. Elevated maternal risk for DS was also observed when plasma Hcy concentration was higher than 4.99 µmol/L. In conclusion, the presence of three or more polymorphic alleles for MTHFR C677T, MTHFR A1298C, MTR A2756G, and RFC1 A80G, and plasma Hcy concentrations higher than 4.99 µmol/L are maternal risk factors for DS.

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Section: Discussionsupporting

confidence: 59%

Genetic polymorphisms involved in folate metabolism and elevated plasma concentrations of homocysteine: maternal risk factors for Down syndrome in Brazil

Biselli

Goloni-Bertollo²,

Zampieri

et al. 2008

Genet. Mol. Res.

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“…The identification of polymorphisms within MTHFR was motivated by the known association between the A222V (677C->T) polymorphism and NTDs in many populations. Furthermore, the identification of a second common polymorphism E429A (1298C->A), in linkage disequilibrium with A222V, has been shown to have NTD association risk in some [van der Put et al, 1998;Richter et al, 2001;De Marco et al, 2002] but not all populations [Parle-McDermott et al, 2003]. Despite the enormous focus on MTHFR, NTD studies and other disease associations have been generally restricted to examining the effect of the presence of one or both of these two common polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Screening for new MTHFR polymorphisms and NTD risk

O’Leary

Mills

Parle‐McDermott

et al. 2005

American J of Med Genetics Pt A

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The enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR) plays a key role in cellular folate metabolism. The A222V (677C->T) polymorphism is a confirmed neural tube defect (NTD) risk factor within Irish and other populations. To search for other unknown single nucleotide polymorphisms (SNPs) that might play a role in the etiology of NTDs, we examined the entire MTHFR coding region in healthy individuals (n = 100). SNPs were identified using sequencing and database analysis and allele frequencies were determined in our Irish population. We identified P39P (116C->T; T allele frequency 0.13) and previously reported R594Q (1793G->A; Q allele frequency 0.07). We screened a large ethnically homogeneous Irish NTD cohort (n>1,300) for P39P and R594Q. A possible association between NTD cases and P39P (P = 0.034) was found but this was not confirmed by transmission disequilibrium testing. R594Q also showed some evidence of a NTD case association (P = 0.07). Further analysis indicated these observations are due to linkage disequilibrium with A222V (677C->T), and therefore these new SNPs are unlikely to be independent risk factors for NTDs. As rates of NTDs differ between ethnic groups, we examined allele and genotype frequencies of P39P and R594Q within African-American and American-Caucasian populations. This is the first NTD association study of both R594Q and the novel P39P. The association with NTD risk reported for these SNPs is driven by the linkage disequilibrium with the A222V (677C->T) NTD risk factor.

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“…In NTD families in Italy and Turkey, the MTHFRA1298C polymorphism was found to be a genetic determinant for NTD risk www.intechopen.com (Boduroğlu et al, 2005;De Marco et al, 2002) but there are conflicting studies in spina bifida occulta patients in Turkey . Other studies have failed to find an association between the 1298A-C polymorphism and risk of NTDs (Parle-McDermott et al, 2003).…”

Section: A1298cmentioning

confidence: 92%