Methylenetetrahydrofolate reductase (MTHFR): incidence of mutations C677T and A1298C in Brazilian population and its correlation with plasma homocysteine levels in spina bifida

Abstract

Homocysteine (Hcy) is converted to cysteine or is remethylated to methionine by methylenetetrahydrofolate reductase (MTHFR). MTHFR plays a central role in the metabolism of folate. Two common polymorphisms in the MTHFR gene (C677T and A1298C) have been described and studies suggest that these polymorphisms are positively associated with the occurrence of spina bifida (SB). Among Brazilians, the incidence of 677T allele homozygosity is 4%. We compared Hcy levels with the genotypes obtained for the mutations C677T and A1298C in the gene MTHFR. Levels of plasma Hcy were higher in children with SB than in controls (average 7.95 vs. 5.55 (micromol/L); P < 0.001). There was no significant difference in the levels of Hcy for these children's mothers and controls (average 7.76 vs. 8.36 (micromol/L); P = 0.27). Eighty one (61.8%) of the affected children were white and 50 (38.2%) were non-white. A similar ratio was observed in the mothers. In the control group, 51 children (40.5%) were white and 75 (59.5%) were non-white, and 52 mothers (41.3%) were white and 74 (58.7%) were non-white. There was no significant difference in the homozygous frequency for the mutated allele 677T among different racial groups. We obtained a prevalence of TT homozygosity of 10/131 (7.64%) in affected children and 13/126 (10.32%) in controls. With respect to the mutation A1298C, the homozygous prevalence for the wild allele was greater among non-white individuals than in white individuals both in case and control groups. Hyperhomocysteinemia is a risk factor for SB. However, in our population, the increase in plasma levels of Hcy is not explained by the presence of the homozygous TT. It is possible that low folic acid intake combined with other genetic factors plays a more important role in the cause of this disease.

5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Acute Lymphoblastic Leukemia Risk: A Meta-analysis

“…In fact, we also previously showed a lack of association between the A1298C genotypes and serum folate, serum cobalamin, or total homocysteine specifically in a mild folate-deficient Brazilian population (9). Indeed, despite some inverse positive associations (33), most current available data suggest no evidence for a major role of this variant in folate status (34) or homocysteine levels (9,35) in populations usually characterized by mild folate deficiency. Given the presence of heterogeneity among study results and the effect in an opposite direction for the A1298C variant found in some reports (22,32), we suggest that no additional studies are needed on this postulated association, at least for populations with adequate folate intake (30,31).…”

Genetics of homocysteine metabolism and associated disorders

“…No differences in MTHFR polymorphisms were identified in mothers, children with NTD or controls (18). Another Brazilian study was also unable to identified MTHFR polymorphism and NTD, suggesting that this gene does not play a role in NTD in the Brazilian population (19).…”

C677T mutation in methylenetetrahydrofolate reductase gene and neural tube defects: Should Japanese women undergo gene screening before pregnancy?

“…A variant of MTHFR 677TT is present in 0% to 34.8% of the healthy population in different ethnic groups: Mexican mestizo exhibited the highest proportion of 34.8% (Mutchinick et al 1999) whereas Brazilian non-white mothers (Perez et al 2003) and South African blacks (Ubbink et al 1999) had the lowest, while homozygosity of the TT genotype in Japanese was 14.5% (Wakai et al 2011). In the present study we compared the frequencies for the TT (minor allele homozygous), CT (heterozygous), and CC (major allele homozygous) genotypes in the 115 SB mothers who had given birth to a sporadic non-familial, non-syndromic spina bifida child with those of the 4517 referent individuals.…”