Maternal metabolic phenotype and risk of down syndrome: Beyond genetics

In 1999, the results of a small case-control study in the United States suggested that the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, associated with an elevation in plasma homocysteine and/or low folate status, may increase the maternal risk of having a child with Down syndrome (DS) (odds ratio, OR1⁄4 2.6) [James et al., 1999]. The authors hypothesized that low folate status, whether due to dietary or genetic factors, could induce centromeric DNA hypomethylation and alterations in chromatin structure that could adversely affect DNA– protein interactions required for centromeric cohesion and meiotic segregation. Although preliminary, these observations challenged the long-held notion that maternal genetics were not associated with DS risk. The possibility of a genetic link stimulated several follow-up studies of the MTHFR 677C>T polymorphism, as well as several other allelic variants in the folate pathway, as possible genetic risk factors for having a child with DS. The ensuing studies originated from several different countries and have yielded inconsistent results. A brief overview of these results is presented below followed by a possible metabolic explanation for the observed inconsistencies among different populations. The initial report by James and colleagues was subsequently expanded to re-evaluate MTHFR, and to evaluate a polymorphism in methionine synthase reductase (MTRR), an enzyme required to maintain normal methionine synthase activity [Hobbs et al., 2000]. In this larger study, a stronger association was found for the MTRR 66A>G variant than for MTHFR 677C>T (OR: 2.57 and 1.91, respectively) and the presence of both polymorphisms conferred a greater risk than either polymorphism alone (OR: 4.08). A study in Ireland similarly demonstrated an increase in DS risk among mothers with the MTRR 66A>G variant. The risk of DS was also further increased by the combined presence of MTRR 66A>G and MTHFR 677 C>T (OR: 2.98); however, no independent increase in risk was associated with the MTHFR polymorphism alone [O’Leary et al., 2002]. Two independent studies of Brazilian mothers found a significant increase in DS risk associated with the MTHFR 677 T allele [Grillo et al., 2002; da Silva et al., 2003]. The da Silva study additionally evaluated three other polymorphisms in the folate pathway, including methionine synthase (MTR 2756 A>C), MTRR 66A>G, MTHFR 1298 A>C, and the cystathionine beta synthase (CBS) 844ins68 in the transsulfuration pathway. Only the MTHFR 677 T allele was associated with increased risk; however, when all five polymorphisms were evaluated together, the mothers of children with DS had a significantly higher number of mutated alleles than did the control mothers. In a case report describing a child affected by both DS and a neural tube defect (NTD), both mother and infant were homozygous for the MTHFR 677 T allele, which was associated with high plasma homocysteine and lymphocyte DNA hypomethylation [Al Gazali et al., 2001]. In a study of Sicilian mothers, the MTR 2756 A>C and MTRR 66A>G polymorphisms, in combination with elevated homocysteine, were significant risk factors for having a child with DS; however, there was no association with either the MTHFR 677 C>T or 1298 A>C polymorphisms [Bosco et al., 2003]. Several other studies have found no association between the MTHFR 677 C>T polymorphism and risk of having a child with DS. For example, independent studies from Italy [Stuppia et al., 2002] and France [Chadefaux-Vekemans et al., 2002] reported no significant difference in the frequency of MTHFR 677 T between DS and control mothers, despite the much higher total population frequency of the MTHFR 677 T allele in these countries. Of related interest, neither country has reported a significant association between MTHFR and maternal risk of NTDs among their populations [Mornet et al., 1997; De Franchis et al., 1998]. Both the Italian and French studies concluded that the relatively high folate intake in the Mediterranean diet could effectively counterbalance the metabolic impact of the MTHFR polymorphism and account for the inability to detect an association with either NTDs or DS, in contrast to countries with lower folate intake. Consistent with a nutritional ‘‘rescue’’ of the MTHFR genotype, the French study found no difference in homocysteine levels among DS or control mothers homozygous for the MTHFR 677 T allele, which is commonly associated with increased homocysteine. *Correspondence to: S. Jill James, Ph.D., Arkansas Children’s Hospital Research Institute, 1120 Marshall St., Slot 824, Little Rock, AR 72202. E-mail: jamesjill@uams.edu