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

Abstract

Abstract. This study aimed to investigate the role of maternal polymorphisms, as well as their risk genotypes combinations of MTR A2756G, MTRR A66G, CBS 844ins68, and RFC A80G, involved in folate/homocysteine metabolism, as possible risk factors for Down syndrome (DS) in Southern Brazil. A case-control study was conducted with 239 mothers of DS children and 197 control mothers. The investigation of polymorphisms was performed by PCR and PCR-RFLP. The distribution of genotypic variants was similar in both groups when they were analyzed separately. An investigation of combined risk genotypes showed that the risk of having a DS child for one, two or three risk genotypes was 6.23, 6.96 and 5.84 (95%CI 1.48-26.26; 1.69-28.66; 1.37-24.86), respectively. The combined MTRR 66G and MTHFR 677T alleles were significantly more common among mothers of children with DS than among control mothers (OR 1.55; IC 95% 1.03-2.35). The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes among MTR, MTRR, CBS and RFC genes are considered maternal risk factors for DS offspring in our population.

Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China

“…Several studies have been conducted on the role of folate gene polymorphisms and metabolism in the pathogenesis of DS to provide evidence and new clues (da Silva et al, 2005;Scala et al, 2006;Wang et al, 2008;Biselli et al, 2008b;Coppedè et al, 2006Coppedè et al, , 2009Neagos et al, 2010;Brandalize et al, 2010). The genes investigated as maternal risk factors for DS include methionine synthase, reduced folate carrier 1 and cystathionine-beta-synthase besides MTHFR and MTRR.…”

“…These results provided further evidence for a major role of gene-gene interactions in the assessment of genetic susceptibility to DS. In the last twenty years, few studies have found the MTHFR C677T polymorphism as an independent risk factor for bearing DS children (James et al, 1999;Hobbs et al, 2000;da Silva et al, 2005;Wang et al, 2007bWang et al, , 2008, and most studies conducted in this field have shown a positive view about the cooperation of MTHFR C677T or A1298C polymorphism with other factors including gene polymorphisms and vitamin intake involved in folate and methyl metabolism (O'Leary et al, 2002;da Silva et al, 2005;Acácio et al, 2005;Rai et al, 2006;Biselli et al, 2008b;Meguid et al, 2008;Coppedè et al, 2006Coppedè et al, , 2009Brandalize et al, 2009Brandalize et al, , 2010, where some of them have been in Chinese populations (Wang et al, 2007b(Wang et al, , 2008Liao et al, 2010). It seems that the MTHFR gene mutation acts as a key factor in the assessment of risk to DS.…”

“…On the other hand, genomic DNA hypomethylation has been causally related to both chromosomal instability and abnormal segregation (Wang et al, 2004;Kim et al, 2011). On the basis of this evidence, several studies from distinct geographic regions have evaluated the role of polymorphisms of folate genes as maternal risk factors for DS (da Silva et al, 2005;Scala et al, 2006;Coppedè et al, 2006;Wang et al, 2008;Brandalize et al, 2010). The most common genes studied in different populations include the methylenetetrahydrofolate reductase (MTHFR) gene, whose product catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methytetrahydrofolate, the methyl donor for the remethylation of homocysteine (Hcy) to methionine, and the methionine synthase reductase (MTRR) gene, encoding an enzyme that maintains the methionine synthase enzyme in an active state for the remethylation of Hcy to methionine.…”

Maternal Age and Oocyte Aneuploidy: Lessons Learned from Trisomy 21

“…Studies conducted in a wide range of North American, South American, European, and Asian populations found signi fi cant associations with either MTHFR c.677C>T, c.1298A>C, MTR c.2756C>G, MTRR c.66A>G, CBS 844ins68, and/or SLC19A1 (also known as RFC-1 ) c.80A>G and the risk of having a child with DS. These studies were extensively reviewed in [ 86 ] and can be combined with more recent studies [87][88][89][90][91] . For example, a recent study on another folate pathway-related gene, the DNA methyltransferase gene DNMT3B, found an association between maternal promoter polymorphisms and DS [ 87 ] .…”

Abnormal Folate Metabolism and Maternal Risk for Down Syndrome

“…Biselli et al, 2008c;Fintelman-Rodrigues et al, 2009), but no association has been found. The conflicting results shown by literature have raised the suggestion that the presence of individual polymorphisms in genes involved in folate metabolism might not increase the risk of having a child with DS, although the effect of combined risk genotypes might modify their individual effect and increase DS risk (J.M., Biselli et al, 2008a;Brandalize et al, 2010;Coppedè et al, 2006;Coppedè et al, 2009;da Silva et al, 2005;Martínez-Frías, et al, 2006;Scala et al, 2006;Wang et al, 2008). Moreover, there is evidence that the significance of genetic polymorphisms seems to depend on interactions with nutritional factors (Papoutsakis et al, 2010;Stover & Caudill, 2008).…”