Relationship between polymorphisms in genes involved in homocysteine metabolism and maternal risk for Down syndrome in Brazil

Am J Med Genet A. 2005 Jun 15;135(3):263-7. doi: 10.1002/ajmg.a.30591.


Associations between specific alleles of genes encoding enzymes in the methionine/homocysteine pathway and plasma homocysteine levels have been examined in different populations. In the present study, we determined polymorphisms of MTHFR A222V (677C > T), MTHFR E429A (1298A > C), MTRR I22M (66A > G), MTR D919G (2756A > G), and CBS 844ins68 and total plasma homocysteine levels (tHcy) among 154 mothers of children with Down syndrome (DS) and 158 control mothers from Brazil. Homocysteine levels were higher among DS mothers compared to control groups (10.437 vs. 8.600 respectively, P = 0.002). Only the 677T allele was associated with altered levels of tHcy in the case group (F((2,153)) = 5.300; P = 0.006), primarily when homozygous. In the control group, the association of the TT genotype with higher levels of tHcy showed borderline significance (F((2,157)) = 2.974; P = 0.054). All genotype distributions were similar in the two groups (P > 0.05), but the frequency of the 677T allele in the case group was significantly higher (chi(2) = 3.862; DF = 1; P = 0.049; OR = 1.437 (1.001-2.062)). Although the 677T allele is associated with increased homocysteine levels, its presence has only a modest impact as an independent risk factor for DS. All the other polymorphisms did not show an association with risk for the syndrome, when evaluated separately (P > 0.05). However, when the presence of 677T, 1298C, 2756G, 66G, and 844ins68 alleles were evaluated together, the mothers of children with DS tend to have a higher number of uncommon alleles than the mothers with no previous affected child.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / metabolism
  • Adolescent
  • Adult
  • Alleles
  • Case-Control Studies
  • Cystathionine beta-Synthase / genetics
  • Cystathionine beta-Synthase / metabolism
  • Down Syndrome / genetics*
  • Enzymes / genetics*
  • Enzymes / metabolism
  • Family Health
  • Female
  • Ferredoxin-NADP Reductase / genetics
  • Ferredoxin-NADP Reductase / metabolism
  • Gene Frequency
  • Genotype
  • Homocysteine / blood
  • Homocysteine / metabolism*
  • Humans
  • Linkage Disequilibrium
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Mothers
  • Polymorphism, Genetic*
  • Risk Factors


  • Enzymes
  • Homocysteine
  • methionine synthase reductase
  • Ferredoxin-NADP Reductase
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Cystathionine beta-Synthase