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

Abstract

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.

Polymorphisms of 5,10-methylenetetrahydrofolate reductase and risk of gastric cancer in a Chinese population: A case-control study

“…35 It is interesting that individuals with homozygous mutations at one site always were homozygous wild-type at the other site, suggesting embryonic selection because of a lethal effect of double homozygotes of these 2 variants or a possible founder effect. This finding is also consistent with those in Caucasians by Stegmann et al 31 In this study, the risk associated with MTHFR 677TT and 677CT genotypes was more pronounced in gastric cardia cancer, which is anatomically adjacent to the esophagus and may share an etiology similar to that of esophageal cancer. 27 This finding suggests different genetic susceptibility to gastric cancer at different sites, which is consistent with the findings of different epidemiologic characteristics, etiology, pathogenesis and clinical behavior reported for gastric cancer at different sites.…”

“…Because the C677T and A1298C variant genotypes affect in vitro MTHFR activity and are correlated with blood homocysteine levels, 23,31 their association with cancer risk is of great interest. The MTHFR enzyme is part of a complex metabolic entity involving both generation of the universal methyl-group donor S-adenosylmethionine and DNA synthesis via the creation of nucleotides.…”

“…In the study reported here, we did not find an association between the MTHFR A1298C polymorphism and risk of gastric cancer, in either all study subjects or different subgroups. Stegmann et al 31 reported that individuals with wild-type 677CC combined with mutant homozygous 1298CC or heterozygous 1298AC showed decreased MTHFR activities, whereas total plasma homocysteine levels were not altered. These data suggest that MTHFR A1298C polymorphism may not play as important a role as C677T in the folate-related process.…”

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia

“…In contrast, for the MLLϩ leukemias, there was no evidence of a protective effect for the A1298C variant (AC ϩ CC, OR ϭ 1.62 with a 95% CI of 0.78-3.36; Table 2). An OR of greater than one indicates that the variant is an ''at risk'' allele; however, it must be noted that the two alleles are in tight negative linkage disequilibrium (28). After adjusting for the nucleotide 677, the A1298C OR falls close to unity (OR ϭ 1.14 with a 95% CI of 0.49-2.73).…”

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

“…These data corroborate several earlier investigations in the field. 3,19,20,33 As the physical distance of 2.1 kb between the two polymorphisms is short, it is not surprising that recombination events very rarely have been observed. 19,34,35 However, these and our results are in apparent contradiction with those reported in two studies by Isotalo et al 21,36 who found a substantial number of combined MTHFR 677TT/1298AC genotypes in adults (approximately 10% of the study participants), 36 neonates (1.7%) 21 and aborted embryos (1.2%), 21 and 677CT/1298CC and 677TT/1298CC genotypes selectively in aborted embryos (3.7%).…”