Since the publication of the first two studies cited in my last post related to this issue, various groups around the world have investigated the association of abnormalities in folate metabolism and methylation pathways and the risk for Down syndrome. Most studies have demonstrated such an association, although specific findings have differed based on the genetic polymorphisms studied and geographic locations of the study populations. Although these ‘inconsistencies’ might at first lead to doubts about the original findings, they probably can be explained by other differences in genetic backgrounds (geographic variations in types and combinations of polymorphisms) and even geographic differences in dietary habits that might alter the overall deleterious effects of the polymorphisms.
For example, we know that the most common gene mutation in MTHFR (C677T) does not completely inactivate the gene, but reduces its efficiency in catalyzing the biochemical reactions of importance. We also know that this deficiency can be overcome by supplementation with folic acid (hence ‘genetic predisposition’ and ‘environmental factors’) and greatly reduces the rates of neural tube defects. Therefore, women in parts of the world where the ‘usual’ diet is rich in folic acid may not necessarily demonstrate an association between MTHFR C677T and Down syndrome, although other genetic polymorphisms in these metabolic pathways, not readily overcome by folic acid alone, might still show a relationship.
Two studies from Italy illustrate my argument in this regard. In 2003, Stuppia and colleagues (Eur J Hum Genet 2003;11:5) reported that they found no significant difference in MTHFR C677T in 64 mothers of Down syndrome babies compared to 112 matched controls. However, a recent study by Scala, et al., (Genet Med 2006;8:409-16) presented a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathways and analyzed risks, not only of the single polymorphisms, but of combinations of these as well as well. They demonstrated significant associations between risk for Down syndrome and the presence of either another MTHFR polymorphism (1298C) or of the reduced-folate-carrier1 (RFC1) 80G gene. Furthermore, although carriers of the MTHFR C6777T polymorphism alone were not found to be at greater risk (supporting the earlier study by Stuppia, et al.), women who carried both the MTHFR C677T and 1298C were at significantly greater risk than those carrying either polymorphism alone. (Another recent study by Acacio, et al. (Prenat Diagn 2005;25:1196-9) from Brazil found women carrying the combination of these same two polymorphisms conferred a 5.7-fold risk for having a baby with Down syndrome).
Chadefaux-Vekemans and colleagues (Pediatr Res 2002;51:766-7) and Bosco, et al. (Am J Med Genet 2203;121:219-24) also found no increased risk associated with MTHFR C677T alone among French women and Sicilian women with Down syndrome babies, but let me remind you, the dietary habits of French, Italian, and Sicilian women, generally, include much higher intakes of folic acid rich foods than that of American women. And, interestingly enough, in the latter study, risk associations were found with both a polymorphism (MTR A2756G) in methionine synthase (3.5-fold risk), yet another enzyme involved in these metabolic pathways, and elevated homocysteine levels (6.7-fold risk). Women who carried both MTR A2756G and MTRR A66G were at 5-fold increased risk.
Other studies from around the world seem to support the association between abnormalities in folic acid/methylation metabolism and the risk for having a baby with Down syndrome, despite population variations. O’Leary and colleagues in Ireland (Am J Med Genet 2002;107:151-5) evaluated both the MTHFR C677T and the MTRR A66G polymorphisms among women who had Down syndrome babies in their country. They too found no correlation MTHFR C677T alone, but found a significant increase in risk in women who carried either one or two copies of the MTRR A66G polymorphism. Furthermore, women who had both the MTHFR C677T (one or two copies) and two copies of the MTRR A66G polymorphisms were at almost 3-fold risk for having a baby with Down syndrome. The only women who had elevated homocysteine levels were those who carried the MTHFR C677T polymorphism, so the increased risk associated with the MTRR A66G polymorphism did not seem to be reflected in the homocysteine levels of their study population. Rai, et al., (J Hum Genet 2006;51:278-83) in India found that women who were homozygous (carried two copies) for either the MTHFR C677T or A1298C polymorphisms had risks 7-fold and 4-fold, respectively, and in the case of the former, all the women who had a Down syndrome baby were less than 31 years of age. No such association between age and Down syndrome risk was found for carriers of MTHFR A1298C.
In my next post, I will wrap up this discussion with some other observations and thoughts related to aneuploidy risk and abnormalities of folic acid/ methylation metabolism and discuss the possible benefits of more widespread awareness of this association…