title: Methionine synthase (MTR) 2756 (A --> G) polymorphism, double heterozygosity methionine synthase 2756 AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteinemia are three risk factors for having a child with Down syndrome.
abstract: Contradictory findings have been recently published on the evaluation of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C-->T) and methionine synthase reductase (MTRR 66 A-->G) as risk factors for having a child with Down syndrome (DS); however, the influence of polymorphisms of methionine synthase (MTR 2756 A-->G) and of MTHFR 1298 A-->C has never been evaluated. In this study, the risk of being a DS case or having a DS child (case mother) was studied by multiple logistic regression analysis of the independent and combined genotypes and of plasma homocysteine, folates, and vitamin B12 in 92 DS cases and 140 control subjects as well as in 63 case mothers and 72 age-matched control mothers from Sicily. (The MTHFR 677 T allele frequency was not different in DS cases and case mothers, compared to the respective control groups). After adjustment for age, total homocysteine (t-Hcys) and MTR 2756 AG/GG genotype were significant risk factors for having a DS child, with odds ratio (OR) of 6.7 (95% CI: 1.4-32.0, P = 0.016) and of 3.5 (95% CI: 1.2-10.9, P = 0.028), respectively. By comparison, MTR 2756 AG/GG genotype increased significantly the risk of being a DS case, with an OR of 3.8 (95% CI: 1.4-10.5, P = 0.009). The double heterozygosity MTR 2756 AG/MTRR 66 AG was the single combined genotype that was a significant risk factor for having a DS child, with an OR estimated at 5.0 (95% CI: 1.1-24.1), after adjustment for t-Hcys. In conclusion, our results provide evidences that homocysteine and MTR genetic polymorphism are two potent risk factors for mothers to have a DS child in Sicily.
authors.affiliation: IRCCS, Oasi Maria S.S.--Institute for Research on Mental Retardation and Brain Aging, Troina (EN), Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bosco
authors.forename: Rosa-Maria
authors.initials: RM
authors.lastname: Guéant-Rodriguez
authors.forename: Guido
authors.initials: G
authors.lastname: Anello
authors.forename: Concetta
authors.initials: C
authors.lastname: Barone
authors.forename: Farès
authors.initials: F
authors.lastname: Namour
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.forename: Antonino
authors.initials: A
authors.lastname: Romano
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D004314:Down Syndrome / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics*; D005420:Flavoproteins; D005492:Folic Acid / Q000097:blood; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012802:Sicily / Q000453:epidemiology
chemical_list: D005420:Flavoproteins; D006710:Homocysteine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase