Maternal polymorphisms 677C-T and 1298A-C of MTHFR, and 66A-G MTRR geness: Is there any relationship between polymorphisms of the folate pathway, maternal homocysteine levels, and the risk for having a child with Down syndrome?

Abstract:

This study was aimed at analyzing the effect of mutations in three non-synonymous SNP genes (677C > T and 1298A > C of the methylenetetrahydrofolate reductase (MTHFR) gene, and 66A > G in the MTRR gene) on total plasmatic homocysteine (Hey), in 91 mothers of Down syndrome (DS) infants and 90 control mothers. The comparison of both groups of mothers is a new way to determine if those mutations and their interactions increase the risk for DS. Material came from the case-control network of the Spanish Collaborative Study of Congenital Malformations (ECEMC). Using a general lineal model in a backwards step, we performed the analyses including the different mutations, maternal age, the fact that each mother had a DS or a control infant, and all possible interactions of these variables, in the models, being maternal Hey the continuous dependent variable. In another model, maternal folic acid intake during the third trimester of pregnancy was added. The results from both models were essentially the same: Hey levels variability differs from case mothers to control ones, the presence of the MTHFR1298A > C polymorphism also affects significantly the Hey variance, as it does the statistical interaction between the mutations MTRR66A > G and MTHFR1298A > C in the mother. In this sense, the interaction between different polymorphisms may totally modify their individual effects, and some of those effects are different in mothers of DS children and in controls' mothers. For instance, only two mutations in MTRR66 (GGAA) in mothers of control infants increase the reference maternal Hey level in 4.66 units, and the individual effect of the genotype with only two mutations in the MTHFR1298 gene (AACC) increases the reference Hey level in 12.74 units. However, the presence of the four mutations (GGCC) interacts giving a statistically significant decrease in 6.00 units in the level of Hey in control mothers. On the contrary, in mothers of DS infants, the sole presence of two mutations in one of these two genes decreases the levels of Hey (-2.31 units for GGAA genotype, and -3.43 units for AACC genotype), while the presence of the four mutations (GGCC) increases Hey in 9.53 units. Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hey in an irreversible way. and that CBS gene is located in chromosome 21, fetuses and infants with DS have functional folate deficiency due to overexpression of CBS. This fact, as well as others influencing Hey levels (such as nutrients interactions and lifestyle), together with the fetal genotype, suggest that their relationship with DS could be through an effect on fetal survival up to birth. Three possible mechanisms are considered by evaluating the results in the light of the present knowledge on cytology and molecular biology. © 2006 Wiley-Liss, Inc.

Año de publicación:

2006

Keywords:

• homocysteine
• Functional polymorphisms
• 66A-G MTRR
• 677C-T MTHFR
• folate
• Methylenetetrahydrofolate reductase
• Methionine synthase reductase
• One-carbon metabolism
• Down syndrome
• 1298A-C MTHFR

Fuente:

scopus