title: Screening for new MTHFR polymorphisms and NTD risk.
abstract: 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.
authors.affiliation: Department of Biochemistry, Trinity College Dublin, Dublin, Ireland. olearyv@tcd.ie
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Leary
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.forename: Anne
authors.initials: A
authors.lastname: Parle-McDermott
authors.forename: Faith
authors.initials: F
authors.lastname: Pangilinan
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.forename: Christopher
authors.initials: C
authors.lastname: Cox
authors.forename: Andrea
authors.initials: A
authors.lastname: Weiler
authors.forename: Mary
authors.initials: M
authors.lastname: Conley
authors.forename: Peadar N
authors.initials: PN
authors.lastname: Kirke
authors.forename: John M
authors.initials: JM
authors.lastname: Scott
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D001483:Base Sequence; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007494:Ireland; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000097:blood / Q000235:genetics*; D009436:Neural Tube Defects / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D009679:Nuclear Family; D011110:Polymorphism, Genetic; D011247:Pregnancy; D012307:Risk Factors
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)