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.

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

“…Seventeen SNPs in 13 candidate genes related to the MTX mechanism of action, purine and pyrimidine synthesis (30)(31)(32), were selected, taking into consideration the following criteria (33,34): validated SNP, SNP causes nonsynonymous amino acid change, indications for clinical relevance from previous publications, and a preferred minimal genotype frequency of ϳ10% (20,21,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”

Maternal Gene Polymorphisms Involved in Folate Metabolism as Risk Factors for Down Syndrome Offspring in Southern Brazil

“…Conflicting results have emerged in studies when evaluating the association between single polymorphisms in genes involved in folate metabolism and risk for DS. It is possible that the combined presence of two or more polymorphisms in the genome could increase the maternal DS risk [3,6,12,15,24,30,31].…”

Abnormal Folate Metabolism and Maternal Risk for Down Syndrome

“…This polymorphism proved to have an impact on enzyme activity resulting in an even more pronounced decrease in its activity in homozygous 1298 CC compared to the heterozygous individuals (van der Putt et al, 1998). In addition to the MTHFR gene, other genetic polymorphisms involved in the folate pathway seem to modulate the maternal risk for bearing a child with DS (Bosco et al, 2003;J.M. Biselli et al, 2008a;Meguid et al, 2008;Pozzi et al, 2009;Sadiq et al, 2011;Scala et al, 2006;Wang et al, 2008) as well as the concentrations of metabolites involved in the folate pathway (Ananth et al 2007;Barbosa et al, 2008;Cheng et al, 2010;Devos et al, 2008).…”

“…Biselli et al, 2008a;Meguid et al, 2008;Pozzi et al, 2009;Sadiq et al, 2011;Scala et al, 2006;Wang et al, 2008) as well as the concentrations of metabolites involved in the folate pathway (Ananth et al 2007;Barbosa et al, 2008;Cheng et al, 2010;Devos et al, 2008). The MTR 2756 A→G polymorphism has been associated with increased maternal risk for DS in the presence of AG or GG genotypes, as well as when combined with polymorphisms MTRR 66 A→G (MTR 2756AG/MTRR 66AG) (Bosco et al, 2003) and MTHFR 677 C→T (MTHFR 677TT/MTR 2756AA). In addition, the allele MTR 2756 G proved to be more frequent, both in homozygosis and heterozygosis, in DS mothers as compared to mothers of individuals without the syndrome (Pozzi et al, 2009).…”