MTRR 66A > G Polymorphism as Maternal Risk Factor for Down Syndrome: A Meta-Analysis Ma ´ rcia R. Amorim 1 and Marcelo A. Costa Lima 2 Down syndrome (DS) is the most common cause of mental retardation. Recent reports have investigated pos- sible genetic factors that may increase maternal risk for DS. Methionine synthase reductase (5-methyltetra- hydrofolate-homocysteine methyltransferase reductase MTRR) plays an important role in folic acid pathway and a common polymorphism (c.66A > G) has been associated with DS but results were controversial. This meta- analysis summarizes the available data concerning this association. Online major databases were searched to identify case-control studies regarding MTRR 66A > G polymorphism and DS. Crude odds ratios (OR) and 95% confidence intervals (CI) were calculated for maternal risk to have a DS child both using fixed and random effects (RE) models. Eleven articles from six populations were identified, including 1226 DS mothers and 1533 control mothers. Heterogeneity among studies was significant (Q = 29.7, DF = 10, p = 0.001; I 2 = 66.3%). The pooled OR in a RE model showed an increase in the risk of having a DS child associated with the G allele (OR 1.23, 95% CI 1.02–1.49). The fixed effect pooled OR was 1.19 (95% CI 1.08–1.31). This meta-analysis indicates that maternal MTRR 66A > G polymorphism is associated with an increased risk of having a DS child. Introduction D own syndrome (DS) is the most common genetic cause of mental retardation in humans. This chromosomal abnormality occurs in 1/700 liveborn infants, with a wide spectrum of clinical phenotypes (Epstein et al., 1991). To date, only maternal age has been associated with an increased risk of DS (Epstein, 2001), however the causative mechanisms involved in the age-dependent occurrence of meiotic mis- segregation are still unclear. The facts that most DS children are born from younger women (Eskes, 2006), and the inci- dence of trisomy of chromosome 21 differs between popula- tions (Wiseman et al., 2009) indicate the concurrence of other genetic components to increase the susceptibility to disjunc- tion errors. It has been proposed that an altered maternal folate me- tabolism could be associated to centromeric DNA hypo- methylation and chromosomal nondisjunction ( James et al., 1999). Abnormal folate metabolism could also counteract the overexpression of the three copies of the cystathionine beta synthase gene (CBS) in the trisomy 21 fetus, assuring folate availability for both DNA synthesis and methylation (Hobbs et al., 2000). From the original paper of James et al. (1999) to date, several reports have investigated the influence of folate pathway polymorphisms on maternal risk for DS and the most studied genes are methylenetetrahydrofolate reductase (MTHFR) and 5-methyltetrahydrofolate-homocysteine me- thyltransferase reductase, also known as methionine syn- thase reductase (MTRR). Results of the association between single nucleotide polymorphisms within these genes and the risk of DS are controversial and discrepancies among reports have been explained mostly by the nutritional environment and genetic characteristics of the populations (Gue ´ant et al., 2003). The MTRR gene was mapped to chromosome 5p15.2–15.3 (Leclerc et al., 1998) and encodes an enzyme responsible for restoration of methionine synthase (MTR) activity by reduc- tive methylation of cobalamin, leading to methionine syn- thesis and production of S-adenosylmethionine, which is the main cellular methyl donor for transmethylation reactions (Wolthers and Scrutton, 2007). A common polymorphism in human MTRR is an adenine to guanine transition at position 66 (c.66A > G), which results in replacement of isoleucine with methionine at residue 22 (p.I22M) (Wilson et al., 1999). This substitution decreases the ability of MTRR to restore MTR activity in vivo (Olteanu et al., 2002). In the last decade several reports have evaluated the as- sociation between MTRR 66A > G polymorphism and an in- creased risk of having a DS child, and the results are controversial. This meta-analysis summarizes published data concerning this association. 1 Departamento de Biologia Geral, Instituto de Biologia, Universidade Federal Fluminense, Nitero ´ i, Rio de Janeiro, Brazil. 2 Departamento de Gene ´tica, Instituto de Biologia Roberto Alca ˆ ntara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 17, Number 1, 2013 ª Mary Ann Liebert, Inc. Pp. 69–73 DOI: 10.1089/gtmb.2012.0200 69