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

Abstract

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.

Comment on ‘increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos’

“…We read with great interest the recent article by Zetterberg et al 1 that examined the potential role of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms in contributing to early spontaneous abortions. Zetterberg et al 1 determined the incidence of C677T and A1298C MTHFR mutations in a study cohort (n=80), which consisted of foetal tissue samples from early spontaneous abortions, and a control group (n=125), which consisted of DNA samples from healthy blood donors that were presumably chosen at random.…”

“…They also observed that MTHFR mutations, taking into account single or multiple mutations, were more common in the foetal group than adult controls (OR of 14.2, P=0.001), suggesting to them that MTHFR mutations may play a significant role in determining foetal viability, especially during times of high folate demand. Zetterberg et al 1 only observed MTHFR mutations in trans positions and did not identify any 677TT/1298AC, 677CT/1298CC or C77TT/1298CC genotype combinations in either their study or control groups. They propose that there is complete linkage disequilibrium between the two common MTHFR polymorphisms, C677T and A1298C, as MTHFR mutations in cis positions were not identified in their study.…”

“…Both study and control groups were from the island of Crete. Using a solid-phase minisequencing technique, Zetterberg et al 1 determined that combined 677TT/1298AA and 677CT/ 1298AC genotypes were observed more frequently in their foetal study group than in their adult control group (Odds ratio [OR] of 2.06, P=0.015). They also observed that MTHFR mutations, taking into account single or multiple mutations, were more common in the foetal group than adult controls (OR of 14.2, P=0.001), suggesting to them that MTHFR mutations may play a significant role in determining foetal viability, especially during times of high folate demand.…”

“…Zetterberg et al 1 determined the incidence of C677T and A1298C MTHFR mutations in a study cohort (n=80), which consisted of foetal tissue samples from early spontaneous abortions, and a control group (n=125), which consisted of DNA samples from healthy blood donors that were presumably chosen at random. In their study group, early spontaneous abortions were defined as foetal deaths that occurred before the twentieth week of gestation.…”

Reply to ‘MTHFR C677T and A1298C polymorphisms and mutated sequences occurring in cis’

“…1 Moreover, we have until now analysed 4500 individuals of Swedish descent and only detected 677T and 1298C alleles in trans configuration (unpublished data). Most studies in the field have reported no or few cases with 677T and 1298C alleles in the cis configuration.…”