Methylation levels at imprinting control regions are not altered with ovulation induction or in vitro fertilization in a birth cohort.

STUDY QUESTION: Do fertility treatments, including ovulation induction (OI), alter epigenetic mechanisms such as DNA methylation at imprinted loci?

SUMMARY ANSWER: We observed small but statistically significant differences in certain imprinting control regions (ICRs) based on the method of conception, however, these small changes in methylation did not correlate to the overall transcriptional levels of the genes adjacent to the ICRs (such as KCNQ1 and SNRPN).

WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Assisted reproductive technology (ART) has been associated with an increase in the risk of rare childhood disorders caused by loss of imprinting (LOI). This study provides novel epigenetic analyses on infants conceived by OI and examines how methylation levels correlate with gene expression.

DESIGN: Data and biospecimens used in this study were from 147 participants of the Epigenetic Birth Cohort comprising 1941 mother-child dyads recruited between June 2007 and June 2009 at the Department of Obstetrics, Gynecology and Reproductive Biology at Brigham and Women's Hospital (BWH) in Boston, MA, USA. Wilcoxon rank-sum tests were used to examine the differences in median percent methylation at each differentially methylated region (DMR) between the spontaneous conception control group and the fertility treatment groups (OI and IVF).

PARTICIPANTS AND SETTING: For each woman who reported IVF we selected a woman who conceived spontaneously matched on age (± 2 years). To increase efficiency, we matched the same controls from the spontaneously conceived group to participants who reported OI. If an appropriate control was not identified that had been previously matched to an IVF participant, a new control was selected. The final analytic sample consisted of 61 spontaneous, 59 IVF and 27 OI conceptions.

MAIN RESULTS AND THE ROLE OF CHANCE: No functionally relevant differences in methylation levels were observed across five (out of six) imprinted DMRs in either the placenta or cord blood of infants conceived with OI or IVF compared with infants conceived spontaneously. While KCNQ1, SNRPN and H19 DMRs demonstrated small but statistically significant differences in methylation based on the method of conception, expression levels of the genes related to these control regions only correlated with the methylation levels of H19.

BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Limitations of our study include the limited sample size, lack of information on OI medication used and culture medium for the IVF procedures and underlying reasons for infertility among OI and IVF patients. We did not perform allele-specific expression analyses and therefore cannot make any inferences about LOI.

GENERALIZABILITY TO OTHER POPULATIONS: These results are likely to be generalizable to non-Hispanic white individuals in populations with similar ART and fertility treatments.