Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects

Abstract

Folic acid administration to women in the periconceptional period reduces the occurrence of neural tube defects (NTDs) in their offspring. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), 677C-->T, is the first genetic risk factor for NTDs in man identified at the molecular level. The gene encoding another folate-dependent enzyme, methionine synthase (MTR), has recently been cloned and a common variant, 2756A-->G, has been identified. We assessed genotypes and folate status in 56 patients with spina bifida, 62 mothers of patients, 97 children without NTDs (controls), and 90 mothers of controls, to determine the impact of these factors on NTD risk. Twenty percent of cases and 18% of case mothers were homozygous for the MTHFR polymorphism, compared to 11% of controls and 11% of control mothers, indicating that the mutant genotype conferred an increased risk for NTDs. The risk was further increased if both mother and child had this genotype. The MTR polymorphism was associated with a decreased O.R. (O.R.); none of the cases and only 10% of controls were homozygous for this variant. Red blood cell (RBC) folate was lower in cases and in case mothers, compared to their respective controls. Having a RBC folate in the lowest quartile of the control distribution was associated with an O.R. of 2.56 (95% CI 1.28-5.13) for being a case and of 3.05 (95% CI 1.54-6.03) for being a case mother. The combination of homozygous mutant MTHFR genotype and RBC folate in the lowest quartile conferred an O.R. for being a NTD case of 13.43 (CI 2.49-72.33) and an O.R. for having a child with NTD of 3.28 (CI 0.84-12.85). We propose that the genetic-nutrient interaction--MTHFR polymorphism and low folate status--is associated with a greater risk for NTDs than either variable alone.

Effect on risk of anencephaly of gene–nutrient interactions between methylenetetrahydrofolate reductase C677T polymorphism and maternal folate, vitamin B12and homocysteine profile

“…However, the control mothers showed no significant difference in biochemical profile as a function of the MTHFR 677C-T polymorphism, probably because there were no differences in folate or vitamin B 12 intake as a function of the genotype. This finding supports the hypothesis that serum levels of folate and vitamin B 12 can be attributed to both genetic and nutritional factors (10,41) .…”

“…However, studies in other countries reported significantly lower RBC folate concentrations in case mothers than in control mothers (10)(11)(12)(38)(39)(40) .…”

“…The 677C-T mutation causes an alanine to valine substitution in the predicted catalytic domain of MTHFR, rendering the enzyme thermolabile, with reduced activity under conditions of low folate concentrations (15) . Homozygosity for the 677T allele is associated with an increase in plasma Hcy levels and a decreased methyltetrahydrofolate pool, predominantly in states of folate, cobalamin and riboflavin (vitamin B 2 ) deficiency (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) . The other polymorphism, 1298A-C, which leads to substitution of an adenine by a cytosine, has also been associated with decreased MTHFR enzyme activity, although not as pronounced as that caused by the 677C-T polymorphism (18,20,21) .…”

Spina bifida and folate-related genes: A study of gene-gene interactions

“…Ideally, such studies also should evaluate interactions with environmental factors, such as blood folate levels 50 and multivitamin supplement use. 51 Other gene-environment 52 and genegene interactions 52,53 might also occur.…”

Neural tube defects in Victoria, Australia: potential contributing factors and public health implications

“…Studies have shown that one particular MTHFR mutation is present in 16% of mothers, 10% of fathers and 13% of children with spina bifida compared with 5% of controls. 39,40 Individuals with elevated homocysteine levels caused by this mutation are prevalent in the population because these levels pose no serious immediate health threat to the carrier parent. However, further evidence is appearing to show that a carrier woman's pregnancy is at risk and perhaps, her cardiovascular health later in life.…”