Whitelaw, N., Bhattacharya, S., Hoad, G., Horgan, G.W., Hamilton, M. and Haggarty, P.
Human Reproduction 29(7), 1452-1458.
||Subfertility is associated with an increased risk of adverse pregnancy outcomes, including epigenetic syndromes. We measured DNA methylation in PEG3, IGF2, SNRPN, LINE-1 and INS in buccal cell DNA from singleton children born following IVF (n=49) and ICSI (n=20) and compared them with a matched spontaneous conception group (n=86). SNRPN methylation in the offspring was linked to the need for fertility treatment.
This effect was specific to children conceived using ICSI and was apparent in the comparison of ICSI versus spontaneous conception (+1.023%; 95%CI 0.088,1.958; p=0.032), ICSI versus standard IVF (+1.112%; 95%CI 0.029,2.194; p=0.044) and ICS versus standard IVF and spontaneous conception (+1.031%; 95%CI 0.136,1.927; p=0.024). In all comparisons the use of ICSI was associated with a higher level of SNRPN methylation in the offspring. A higher level of SNRPN methylation in the offspring was also associated with a longer duration of infertility in the parents. This was observed in all cases of infertility (p=0.026) and after excluding the ICSI cases (p=0.017). There was a significant increase in the level of LINE1 methylation with age between birth and 7 years (+0.8 95%CI 0.5,1.0 % per year; p<0.001). The INS gene decreased significantly over the same period (-0.5 95%CI -0.9,-0.04 % per year; p=0.032). There was no evidence of change in any of the imprinted genes over the same period.
These results suggest that there may be gene specific changes in imprinting methylation in the offspring of men requiring ICSI as part of infertility treatment. Altered methylation in same gene also appears to be associated with the severity of infertility in the parents irrespective of the method of treatment. Once set the level of methylation within the imprinted genes is stable with age over at least the first seven years of life. The mechanisms underpinning such epigenetic changes in the offspring and their long term consequences merit further study.