title: Association of maternal polymorphisms in folate metabolizing genes with chromosome damage and risk of Down syndrome offspring.
abstract: We analyzed the role of six common polymorphisms in folate metabolizing genes as possible risk factors for having a child with Down syndrome (DS) in 94 Italian mothers of a DS child (MDS) and 113 matched control mothers, both aged less than 35 years at conception. Investigated polymorphisms include methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C, methionine synthase (MTR) 2756A>G, methionine synthase reductase (MTRR) 66A>G, and thymidylate synthase (TYMS) 28bp repeat and 1494del6. We also measured the amount of chromosome damage in peripheral blood lymphocytes of 42 MDS and 41 matched controls, by means of the micronucleus assay, and searched for association between this cytogenetic endpoint and any of the studied polymorphisms. Micronuclei in peripheral blood lymphocytes have been analyzed several years after conception: the mean age at sampling was 45.6+/-11.4 years for MDS and 47.95+/-6.9 years for controls. The combined MTHFR 677TT/MTR 2756AA genotype was associated with increased DS risk (P=0.034), and the combined MTHFR 1298AC/TYMS 2R/2R genotype with reduced risk (P=0.003). Moreover, we observed a significant increased frequency of micronucleated lymphocytes in MDS as compared to controls (P<0.0001) and, in the total population, a significant correlation between micronucleated cells and both MTHFR 677C>T (P=0.031) and 1298A>C (P=0.047) polymorphisms.
authors.affiliation: Department of Neuroscience, University of Pisa, Pisa, Italy. f.coppede@geog.unipi.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Coppedè
authors.forename: Francesca
authors.initials: F
authors.lastname: Migheli
authors.forename: Stefania
authors.initials: S
authors.lastname: Bargagna
authors.forename: Gabriele
authors.initials: G
authors.lastname: Siciliano
authors.forename: Ivana
authors.initials: I
authors.lastname: Antonucci
authors.forename: Liborio
authors.initials: L
authors.lastname: Stuppia
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Palka
authors.forename: Lucia
authors.initials: L
authors.lastname: Migliore
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000328:Adult; D000367:Age Factors; D016022:Case-Control Studies; D002875:Chromosomes / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D048629:Micronuclei, Chromosome-Defective; D008875:Middle Aged; D009034:Mother-Child Relations; D011110:Polymorphism, Genetic / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase