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

A number of studies have demonstrated that the common polymorphism 677C-->T in the gene encoding 5, 10-methylenetetrahydrofolate reductase (MTHFR) lea ds to a thermolabile variant with decreased enzyme activity and to mildly e levated plasma homocysteine. 677TT homozygosity was shown to be more freque nt in NTD probands compared with controls in some studies. Recently, anothe r polymorphism, 1298A-->C, in the MTHFR gene was described and combined het erozygosity 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 indi viduals tested, we developed an easy-to-perform ARMS-RFLP test. Our data sh ow that the two polymorphisms are in linkage disequilibrium in the general population and in NTD individuals. There was no statistically significant d ifference in allele and genotype frequency between probands (patients, fetu ses) and controls (P > 0.10) and between observed and expected values for m other-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 tran smission rates do not deviate significantly from equilibrium (P > 0.50). Th us, our data provide no evidence for an association between NTD phenotype a nd MTHFR 677C/T-1298A/C genotypes and haplotypes. Am. J. Med. Genet. 87:23- 29, 1999. (C) 1999 Wiley-Liss, Inc.