Response to “Folate Gene Polymorphisms and the Risk of Down Syndrome Pregnancies in Young Italian Women” by Coppedè et al. [2006]

We read with interest the article by Coppedè et al. [2006], entitled ‘‘Folate Gene Polymorphisms and the Risk of Down Syndrome Pregnancies in Young Italian Women. ’’ The article explored gene–gene interactions among the methylenetetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C polymorphisms and the reduced folate carrier (RFC1) 80 G>A polymorphism as risk factors for a Down syndrome (DS) offspring in a group of mothers from central Italy. Specifically, a significant inverse association with the risk of having a DS child was found for the combined MTHFR 1298 AA/RFC1 80 GA or AA genotype, compared with the 1298 AA/ 80 GG genotype (OR 0.36, 95% CI 0.14–0.96). We recently published a study on seven homocysteine/folate gene polymorphisms as risk factors for DS in a population from the Campania region (Southern Italy) [Scala et al., 2006]. We found that the MTHFR 1298 C and RFC1 80 G polymorphisms (alleles or genotypes) were associated with increased risk of DS, particularly in the population subgroup belonging to the upper age quartile ( 34 years at conception), and that positive interactions existed for the following alleles or genotypepairs: MTHFR 677TT and 1298CC/CA, MTHFR 1298CC/CA and RFC1 80 GG/GA, RFC1 80 GG and methylenetetrahydrofolate-dehydrogenase 1958AA. It is interesting to note that the data from the two studies are complementary: indeed, in our study the presence of the 1298 C and the 80 G alleles at one or two loci was associated with an increased risk of DS, while in Coppedè at al. the 1298 AA/80 GA or AA genotype was associated with protection. Re-analyzing the data of our study population (STATA software, version 7.0 SE), we replicated the result of Coppedè et al. of an inverse association between the MTHFR 1298 AA/RFC1 80 GA or AA genotype and the risk of DS. In addition, a reduced risk of DS was associated not only with the genotype pair MTHFR 1298 AA/RFC1 80 GA or AA (OR 0.44, 95% CI 0.2–0.99), but also with the genotype pair 1298AA/80AA (OR0.32, 95%CI 0.12–0.85) (Table I). A similar analysis in the age group less than 35 years at conception (52 cases and 106 controls) did not show any significant association, while a more pronounced effect was observed in the age group 35 years at conception (1298 AA/80 AA, two cases and seven controls vs. 1298 AA/80 GG, five cases and two controls: OR 0.11, 95% CI 0.01–1.11; P1⁄4 0.06). However, the pooled estimate of the data from the two studies for the age group <35 years resulted in a significant inverse association with the risk of DS not only for the genotype combination 1298 AA/80GA or AA, statistically significant in Coppedè et al., but also for the 1298 AA/80AA genotype (Table II). As the 1298 CC/80 GG genotype may be a better reference than 1298 AA/80 GG to assess a protective role of the genotype combination 1298AA/80AA,we compared all the possible MTHFR/RFC1 genetic combinations with the new referent genotype. The analysis showed that the 1298 AA/80 AA genotype (vs. 1298 CC/80 GG) had an inverse association with the risk of DS, with a tendency toward significance (OR 0.31, 95% CI 0.08–1.15; P1⁄4 0.08). These