Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects(NTD)

Am J Med Genet. 1999 Nov 5;87(1):23-9.


A number of studies have demonstrated that the common polymorphism 677C-->T in the gene encoding 5, 10-methylenetetrahydrofolate reductase (MTHFR) leads to a thermolabile variant with decreased enzyme activity and to mildly elevated plasma homocysteine. 677TT homozygosity was shown to be more frequent in NTD probands compared with controls in some studies. Recently, another polymorphism, 1298A-->C, in the MTHFR gene was described and combined heterozygosity 677CT/1298AC was suggested to be an additional risk factor for NTD. The present study examines the genotype and haplotype distribution of the two polymorphisms in the German population and evaluates the impact on NTD individuals and their relatives. To determine the haplotype of all individuals tested, we developed an easy-to-perform ARMS-RFLP test. Our data show that the two polymorphisms are in linkage disequilibrium in the general population and in NTD individuals. There was no statistically significant difference in allele and genotype frequency between probands (patients, fetuses) and controls (P > 0.10) and between observed and expected values for mother-child pairs (P > 0.80). Taking into account gender, an increased rate of 677CT heterozygotes was found in affected and unaffected males compared to affected and unaffected females. A family-based association study using a multiallelic transmission disequilibrium test (TDT) also shows that transmission rates do not deviate significantly from equilibrium (P > 0.50). Thus, our data provide no evidence for an association between NTD phenotype and MTHFR 677C/T-1298A/C genotypes and haplotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Case-Control Studies
  • DNA / analysis
  • DNA / genetics
  • Family Health
  • Female
  • Fetus
  • Gene Frequency
  • Genotype
  • Germany
  • Haplotypes
  • Humans
  • Linkage Disequilibrium*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Mutation
  • Neural Tube Defects / embryology
  • Neural Tube Defects / enzymology
  • Neural Tube Defects / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Pedigree
  • Polymorphism, Genetic
  • Population Surveillance


  • DNA
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)