I read with interest the article, “Maternal polymorphisms for methyltetrahydrofolate reductase and methionine synthetase reductase and risk of children with Down syndrome” and congratulate the authors for such a nice paper. The authors investigated the C677T polymorphism in the methylenetetrahydrofolate reductase gene ( MTHFR ) and the A66G polymorphism in the methionine synthase reductase gene ( MTRR ) as possible maternal risk factors for having a child with Down syndrome (DS) in a case-control population from northern Italy, observing that the MTRR A66G polymorphism, but not the MTHFR C677T, was associated with increased DS risk.

Interactions between the 2 polymorphisms did not modify DS risk. Three other studies have been performed in Italy aimed at addressing the possible contribution of both MTHFR C677T and MTRR A66G polymorphisms in DS risk, the first in Sicily, the second in southern Italy, and the latter by us in central Italy.

All these studies agree that the MTHFR C677T polymorphism is not an independent DS risk factor and that interactions between MTHFR C677T and MTRR A66G do not increase DS risk in the Italian population, but none of them observed a statistically significant independent association between the MTRR A66G polymorphism and DS risk. However, even if not statistically significant, we recently observed an increased odds ratio for the mutant MTRR 66GG genotype in MDS from central Italy (odds ratio, 1.60; 95% confidence interval, 0.69–3.66). Moreover, Bosco et al observed that the double-heterozygosity methionine synthase ( MTR ) 2756AG/ MTRR 66AG increased significantly maternal DS risk in Sicily (odds ratio, 5.0; 95% confidence interval, 1.1–24.1).

Overall, these data suggest that we cannot exclude a role for the MTRR A66G polymorphism in modifying DS risk, likely when interacting with other genetic and/or environmental factors. The identification by Pozzi et al of a case-control population in whom the MTRR A66G genotype has a significant impact on DS risk is of great interest to me, and I would encourage the authors to continue their investigation searching for genetic factors, other than MTHFR C677T, and environmental-dietary factors interacting with MTRR 66G and explaining the increased DS risk associated with this allele in their population. This could be of real interest to better address the still controversial contribution of this polymorphism to DS risk.