The methylenetetrahydrofolate reductase c.c.677 C>T and c.c.1298 A>C polymorphisms in reproductive failures: Experience from an RSA and RIF study on a Polish population.

Izabela Nowak,Małgorzata Banasik,Maciej Sobczyński,Paweł Radwan,Andrzej Malinowski,Jacek R Wilczyński,Michał Radwan,Aleksandra Bylińska,Hanna Motak-Pochrzęst,Karolina Wilczyńska,Piotr Kuśnierczyk,Ewa Barcz,Andrzej Wiśniewski,Rafał Płoski,Joël R Drevet

doi:10.1371/journal.pone.0186022

Abstract

Almost 1600 individuals from the Polish population were recruited to this study. Among them 319 were fertile couples, 289 were recurrent spontaneous abortion (RSA) couples, and 131 were in the group of recurrent implantation failure (RIF) following in vitro fertilization. The aim of this study was to evaluate the MTHFR c.c.677 C>T and c.c.1298 A>C polymorphisms’ association with RSA and RIF. We used PCR-RFLP with HinfI (677 C>T) and MboII (1298 A>C) digestion. We observed a protective effect of the female AC genotype (OR = 0.64, p = 0.01) and the C allele (AC+CC genotypes; OR = 0.65, p = 0.009) against RSA. Moreover, 1298 AA/677 CT women were more frequent in RSA (31.14%) and RIF (25.20%) groups in comparison to fertile women (22.88%), although this difference was significant only in the case of RSA (p = 0.022, OR = 1.52). Male combined genotype analysis revealed no association with reproductive failure of their partners. Nevertheless, the female/male combination AA/AC of the 1298 polymorphism was more frequent in RSA couples (p = 0.049, OR = 1.49). However, the significant results became insignificant after Bonferroni correction. In addition, analysis of haplotypes showed significantly higher frequency of the C/C haplotype (1298 C/677 C) in the female control group than in the female RSA group (p = 0.03, OR = 0.77). Moreover, the association between elevated homocysteine (Hcy) level in plasma of RSA and RIF women and MTHFR polymorphisms was investigated but did not reveal significant differences. In conclusion, for clinical practice, it is better to check the homocysteine level in plasma and, if the Hcy level is increased, to recommend patients to take folic acid supplements rather than undergo screening of MTHFR for 1298 A>C and 677 C>T polymorphisms.

Highlights

Nowadays, recurrent spontaneous abortion (RSA) and recurrent implantation failure after in vitro fertilization (RIF) are implicated as the most frustrating clinical conditions for both couples who have problems with conceiving and maintaining pregnancy and for doctors who cannot help patients, especially in RIF cases [1]
In this study we aimed to investigate whether genetic methylenetetrahydrofolate reductase (MTHFR) polymorphisms in 1298 A>C and 677 C>T are associated with reproductive failure, namely RSA and RIF
We tried to elucidate the effect of MTHFR polymorphism on the homocysteine level in plasma of RSA and RIF patients

Summary

Introduction

Recurrent spontaneous abortion (RSA) and recurrent implantation failure after in vitro fertilization (RIF) are implicated as the most frustrating clinical conditions for both couples who have problems with conceiving and maintaining pregnancy and for doctors who cannot help patients, especially in RIF cases [1]. Natural conception in the female body remains to some extent an enigmatic phenomenon, whereas in vitro fertilization (IVF) with subsequent embryo transfer provides clinicians some information about when the embryo was transferred and whether implantation has occurred. Clinicians are still observing increasing numbers of RSA and RIF cases and they are implementing expanded diagnostics in the quest for the cause of this situation as soon as a woman experiences 2 consecutive miscarriages or cannot become pregnant after a repeated IVF. The RIF prevalence rate in women following IVF treatment is approximately 10% [4]

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