Methylation pathway gene polymorphisms associate with in vitro fertilization (IVF) outcomes

Abstract

ObjectiveStudies suggest that IVF can alter the epigenetic processes of imprinting and methylation of DNA. The short and long-term consequences of this remain to be elucidated. It is well known that, prior to activation of the paternal genome, the oocyte alone controls the early development of the preimplantation embryo. Because enzymes of the methylation pathway are expressed in the oocyte, and are critical to development, we hypothesized that polymorphisms in this pathway could associate with IVF outcome.DesignProspective cohort study.Materials and methodsGenotyping of several polymorphisms in methylation cycle genes was performed on 240 women in a University setting whose oocytes were used for IVF from July 2005-May 2006. Multivariate analysis was performed to assess whether these polymorphisms associated with implantation (sac), ongoing pregnancy (>12 weeks) or miscarriage. A secondary multivariate analysis was performed to determine whether the polymorphisms associated with embryo quality, as determined by growth (cell number) and fragmentation.ResultsThe odds of implantation for the six polymorphisms tested are shown. The polymorphism in the adenosine kinase gene (ADK) at position 442 was associated with overall implantation: the age-adjusted odds decreased with the homozygote mutant compared to the heterozygote (AOR = 0.42; P=0.004) or wild type (AOR = 0.45; P=0.008). Although the remaining polymorphisms were not significantly associated with implantation, trends were observed for MTRR 524, BHMT 717, and DNMT1 1267. Additionally, the MTRR 524 polymorphism was associated with significantly fewer spontaneous losses (AOR = 3.76; P=0.004) and a higher on-going pregnancy rate (P=0.035). No association was noted between the polymorphisms tested and embryo quality to account for this difference.Conclusions ObjectiveStudies suggest that IVF can alter the epigenetic processes of imprinting and methylation of DNA. The short and long-term consequences of this remain to be elucidated. It is well known that, prior to activation of the paternal genome, the oocyte alone controls the early development of the preimplantation embryo. Because enzymes of the methylation pathway are expressed in the oocyte, and are critical to development, we hypothesized that polymorphisms in this pathway could associate with IVF outcome. Studies suggest that IVF can alter the epigenetic processes of imprinting and methylation of DNA. The short and long-term consequences of this remain to be elucidated. It is well known that, prior to activation of the paternal genome, the oocyte alone controls the early development of the preimplantation embryo. Because enzymes of the methylation pathway are expressed in the oocyte, and are critical to development, we hypothesized that polymorphisms in this pathway could associate with IVF outcome. DesignProspective cohort study. Prospective cohort study. Materials and methodsGenotyping of several polymorphisms in methylation cycle genes was performed on 240 women in a University setting whose oocytes were used for IVF from July 2005-May 2006. Multivariate analysis was performed to assess whether these polymorphisms associated with implantation (sac), ongoing pregnancy (>12 weeks) or miscarriage. A secondary multivariate analysis was performed to determine whether the polymorphisms associated with embryo quality, as determined by growth (cell number) and fragmentation. Genotyping of several polymorphisms in methylation cycle genes was performed on 240 women in a University setting whose oocytes were used for IVF from July 2005-May 2006. Multivariate analysis was performed to assess whether these polymorphisms associated with implantation (sac), ongoing pregnancy (>12 weeks) or miscarriage. A secondary multivariate analysis was performed to determine whether the polymorphisms associated with embryo quality, as determined by growth (cell number) and fragmentation. ResultsThe odds of implantation for the six polymorphisms tested are shown. The polymorphism in the adenosine kinase gene (ADK) at position 442 was associated with overall implantation: the age-adjusted odds decreased with the homozygote mutant compared to the heterozygote (AOR = 0.42; P=0.004) or wild type (AOR = 0.45; P=0.008). Although the remaining polymorphisms were not significantly associated with implantation, trends were observed for MTRR 524, BHMT 717, and DNMT1 1267. Additionally, the MTRR 524 polymorphism was associated with significantly fewer spontaneous losses (AOR = 3.76; P=0.004) and a higher on-going pregnancy rate (P=0.035). No association was noted between the polymorphisms tested and embryo quality to account for this difference. The odds of implantation for the six polymorphisms tested are shown. The polymorphism in the adenosine kinase gene (ADK) at position 442 was associated with overall implantation: the age-adjusted odds decreased with the homozygote mutant compared to the heterozygote (AOR = 0.42; P=0.004) or wild type (AOR = 0.45; P=0.008). Although the remaining polymorphisms were not significantly associated with implantation, trends were observed for MTRR 524, BHMT 717, and DNMT1 1267. Additionally, the MTRR 524 polymorphism was associated with significantly fewer spontaneous losses (AOR = 3.76; P=0.004) and a higher on-going pregnancy rate (P=0.035). No association was noted between the polymorphisms tested and embryo quality to account for this difference. Conclusions