Impact of fertility status on epigenetic indicators of future health risk

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PROJECT SUMMARY Infertility affects approximately 10% of women in the United States and is increasingly becoming more common. Recent studies suggest that, in addition to its reproductive consequences, infertility is associated with the development of chronic disease and all-cause mortality. Two examples of this phenomenon that are supported by the literature are risks of cardiovascular disease (CVD) and metabolic syndrome (MetS), both of which are more common in women and have elevated risks after menopause. CVD is the leading cause of death in women, and MetS has a prevalence of approximately 30% and increases risk for mortality. It is likely that there are shared pathways between infertility and CVD and MetS, such as increased inflammation, which may modulate risk for both conditions. Thus evaluating women with infertility for future CVD and MetS provides a unique opportunity for preventative measures and personalized treatments within the context of infertility evaluations. One way to identify women at increased risk for CVD and MetS is through examining differences in DNA methylation. DNA methylation is one mechanism through which gene expression responds to changes in the environment, hormone status, or other physiologic processes. These changes may occur prior to the onset of symptomatic disease and can identify women at increased risk for adverse outcomes. This study will evaluate three DNA methylation-based predictors of long-term health, CVD, and MetS in 125 women with infertility and 125 women without infertility who are undergoing in vitro fertilization. We will also evaluate associations with low ovarian reserve, which is predictive of time to menopause and may also associate with increased risk. First, we will assess an indicator of cellular age acceleration that is predictive of health-span and all-cause mortality. Then, we will leverage combinations of CpG sites to predict a CVD methylation risk score and a separate MetS methylation risk score. We hypothesize that infertility and low ovarian reserve will be associated with increased age acceleration, which would serve as a general marker of future disease and mortality. We hypothesize that the CVD methylation risk score will be associated with infertility and low ovarian reserve due to putative links between infertility and later development of CVD. Finally, we hypothesize that infertility and low ovarian reserve will be associated with increased MetS methylation risk scores as obesity and other MetS risk factors play a role in infertility. If successful, this proposal would provide further evidence that infertility is linked to other long-term health conditions, and would identify a predictive marker of future disease that could be evaluated as part of treatment for infertility. This proposal will also inform subsequent R01 submissions to further establish non-reproductive impacts of infertility and allow for follow-up until disease onset.