Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis

Abstract

The common 677C-->T mutation (+) in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme, has been associated with spina bifida neural tube defects (NTD). We combined all known Dutch control groups, a total of 1273 individuals, and found a prevalence of the 677C-->T mutation of 8.4%. When compared with the frequencies in 55 SB patients and to mothers with a child with SB their parents, this gave an OR of 1.9 [95% CI 1.1-3.3] for mothers and an OR of 1.5 [95% CI 0.74-3.1] for patients. The frequency of this mutation and its associated risk for NTD may be population-dependent. However, the frequencies of the 677C-->T mutation in different national and international control groups are almost all in the same range. We therefore combined the observed frequencies of the 677C-->T mutation in all reported studies. The mutation was present in 9.2% of controls, resulting in ORs for all reported NTD patients and their parents of: 1.7 [95% CI: 1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and NTD patients (combined prevalence 16.4%), respectively, vs. all international controls. This meta-analysis confirms that the 677C-->T mutation is a genetic risk factor for NTD.

MTHFR677TT genotype and disease risk: is there a modulating role for B-vitamins?

“…The reduced activity of the MTHFR enzyme in individuals with the MTHFR 677TT genotype, decreases the availability of 5-methyltetrahydrofolate which plays a key role in methylation (10) and decreases global DNA methylation (63,64) ; therefore, it is no surprise that this specific mutant gene has been extensively investigated as a genetic risk factor for NTD (65,66) . Over the past two decades, several reports have shown a 2 to 4-fold increased risk of NTD if the infant or the mother has the MTHFR 677TT genotype (65,(67)(68)(69)(70) . van der Put et al (71) reported an even higher risk of an NTD pregnancy if both the mother and the fetus were homozygous for the MTHFR 677C T polymorphism.…”

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population

“…The best-characterized MTHFR genetic polymorphism is a 677CAET transition that affects the predicted catalytic domain of the MTHFR protein. This mutation, resulting in decreased enzyme activity, is associated with mildly elevated plasma homocysteine levels and a redistribution of folates, namely, elevated red cell folate and lowered plasma folate (van der Put et al 1995(van der Put et al , 1996. Homozygosity for the 677T mutation predisposes individuals to the development of hyperhomocysteinemia, especially during times of folate insufficiency van der Put et al 1998).…”

“…Therefore, the two MTHFR polymorphisms (677CAET and 1298AAEC) have been widely investigated as genetic risk factors for NTDs. Although the MTHFR C677T mutation is considered a genetic risk factor for NTD by some (Kirke et al 1993;Mills et al 1995;van der Put et al 1995van der Put et al , 1996van der Put et al , 1997aWhitehead et al 1995;Ou et al 1996), there are studies that could not Abstract Homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for neural tube defects (NTDs) in many populations, including Italians. Another common mutation on the MTHFR gene, A1298C, has also been described as a risk mutation.…”

C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses

“…Furthermore, the mutation has been shown to be a risk factor for premature cardiovascular disease 3,4 and neural tube defect. 5,6 Deficient activity of MTHFR may also be associated with psychiatric conditions such as mental retardation, schizophrenia, 7-9 and affective disorders. 10 In line with this, a recent study of Arinami et al 1 examined the C677T polymorphism for patients with schizophrenia, bipolar disorder, and depression, and found an increased frequency of homozygosity for the T677 allele among schizophrenics (odds ratio 1.9, P = 0.0006) and among patients with unipolar depression (odds ratio 2.8, P = 0.005), but not among patients with bipolar disorder (odds ratio 1.0).…”