Maternal polymorphisms 677C‐T and 1298A‐C of MTHFR, and 66A‐G MTRR genes: 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 (Hcy), 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 Hcy 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: Hcy levels variability differs from case mothers to control ones, the presence of the MTHFR1298A > C polymorphism also affects significantly the Hcy 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 Hcy level in 4.66 units, and the individual effect of the genotype with only two mutations in the MTHFR1298 gene (AACC) increases the reference Hcy 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 Hcy 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 Hcy (-2.31 units for GGAA genotype, and -3.43 units for AACC genotype), while the presence of the four mutations (GGCC) increases Hcy in 9.53 units. Taking into consideration that in the one-carbon metabolism cystathionine beta-synthase (CBS) catalyzes Hcy 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 Hcy 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.

Maternal gene polymorphisms involved in folate metabolism and risk of Down syndrome offspring: a meta-analysis

“…In addition, the lack of association between the studied gene polymorphisms and DS might be due to other unidentified loci that are probably in linkage disequilibrium and affect the risk of developing DS. Risk effect may depend on gene methylation, and thus gene-environment interactions between the genotypes and dietary intake, and in particular folic acid consumption, may be crucial to maintaining or altering the effects of the polymorphic variants (Martinez-Frias et al 2006). Sampling variability and stratification in case-control study design can be a possible confounding factor in the role of genetic markers.…”

“…The mechanism underlying the meiotic nondisjunction is poorly understood and is thought to have a multifactorial aetiology, being influenced by both genetic and acquired factors (James et al 1999;Martinez-Frias et al 2006).…”

Association of MTHFR and RFC1 gene polymorphism with hyperhomocysteinemia and its modulation by vitamin B12 and folic acid in an Indian population

“…MTHFR, A1298C, is also a risk factor in these disorders though to a lesser degree (Martinez-Frias et al, 2006). However, in normal populations the frequency of T homozygosity of C677T, swings from 1% (Africa, Southeast Asia) to around 30% (Europe, Americas), suggesting that the SNPs have different selective potential in different populations (Rosenberg et al, 2002;GueantRodriguez et al, 2006;Zee et al, 2007).…”

Toward optimal set of single nucleotide polymorphism investigation before IVF

“…Free homocysteine is quite toxic compound that violates the integrity of the vascular endothelium. These properties determine the fact that the increased level of free homocysteine is one of the precipitating factors in the development of a number of multifactorial diseases: violation of embryonic development [45], metabolic syndrome (primarily atherosclerosis), lymphomas, all kinds of cardiovascular diseases [46], disorders of pregnancy, autism, Alzheimer's disease [47]. Equilibrium between methionine and homocysteine also defines the correct flow of the fundamental processes such as synthesis of nucleotides and DNA methylation.…”