Racial Differences in DNA Methylation-Based Age Acceleration in Preeclamptic and Normotensive Pregnancy

Background: Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. Chronological age and race are associated with increased risk of preeclampsia; however, the pathophysiology of preeclampsia and how these risk factors impact its development, are not entirely understood. This gap precludes clinical interventions to prevent preeclampsia occurrence or to address stark racial disparities in maternal and neonatal outcomes. Of note, cellular aging rates can differ between individuals and chronological age is often a poor surrogate of biological age. DNA methylation age provides a marker of biological aging, and those with a DNA methylation age greater than their chronological age have "age acceleration". Examining age acceleration in the context of preeclampsia status, and race, could strengthen our understanding of preeclampsia pathophysiology, inform future interventions to improve maternal/neonatal outcomes, and provide insight to racial disparities across pregnancy. Objectives: The purpose of this exploratory study was to examine associations between age acceleration, preeclampsia status, and race across pregnancy. Study design: This was a longitudinal, observational, case-control study of 56 pregnant individuals who developed preeclampsia (n=28) or were normotensive controls (n=28). Peripheral blood samples were collected at trimester-specific time points and genome-wide DNA methylation data were generated using the Infinium MethylationEPIC Beadchip. DNA methylation age was estimated using the Elastic Net "Improved Precision" clock and age acceleration was computed as {Delta}age, the difference between DNA methylation age and chronological age. DNA methylation age was compared with chronological age using scatterplots and Pearson correlations, while considering preeclampsia status and race. The relationships between preeclampsia status, race, and {Delta}age were formally tested using multiple linear regression, while adjusting for pre-pregnancy body mass index, chronological age, and (chronological age)2. Regressions were performed both with and without consideration of cell-type heterogeneity. Results: We observed strong correlations between chronological age and DNA methylation age in all trimesters, ranging from R=0.91-0.95 in cases and R=0.86-0.90 in controls. We observed significantly stronger correlations between chronological age and DNA methylation age in White versus Black participants ranging from R=0.89-0.98 in White participants and R=0.77-0.83 in Black participants. We observed no association between {Delta}age and preeclampsia status within trimesters. However, even while controlling for covariates, {Delta}age was higher in trimester 1 in participants with higher pre-pregnancy BMI ({beta}=0.12, 95% CI=0.02 to 0.22, p=0.02) and lower in Black participants relative to White participants in trimesters 2 ({beta}=-2.68, 95% CI=-4.43 to -0.94, p=0.003) and 3 ({beta}=-2.10, 95% CI=-4.03 to -0.17, p=0.03). When controlling for cell-type heterogeneity, the observations with BMI in trimester 1 and race in trimester 2 persisted. Conclusions: We report no association between {Delta}age and preeclampsia status, although there were associations with pre-pregnancy BMI and race. In particular, our findings in a small sample demonstrate the need for additional studies to not only investigate the complex pathophysiology of preeclampsia, but also the relationship between race and biological aging, which could provide further insight into racial disparities in pregnancy and birth. Future efforts to confirm these findings in larger samples, including exploration and applications of other epigenetic clocks, is needed.