RÉSUMÉ
STUDY QUESTION: Are reproductive characteristics associated with genome-wide DNA methylation and epigenetic age? SUMMARY ANSWER: Our data suggest that increasing parity is associated with differences in blood DNA methylation and small increases in epigenetic age. WHAT IS KNOWN ALREADY: A study of 397 young Filipino women (ages 20-22) observed increasing epigenetic age with an increasing number of pregnancies. STUDY DESIGN, SIZE, DURATION: We used data from 2356 non-Hispanic white women (ages 35-74) enrolled in the Sister Study cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on reproductive history were ascertained via questionnaire. Of the 2356 women, 1897 (81%) reported at least one live birth. Among parous women, 487 (26%) women reported ever experiencing a pregnancy complication. Three epigenetic clocks (i.e. Hannum, Horvath and Levine) and genome-wide methylation were measured in DNA from whole blood using Illumina's HumanMethylation450 BeadChip. We estimated association ß-values and 95% CIs using linear regression. MAIN RESULTS AND THE ROLE OF CHANCE: All three epigenetic clocks showed weak associations between number of births and epigenetic age (per live birth; Hannum: ß = 0.16, 95% CI = 0.02, 0.29, P = 0.03; Horvath: ß = 0.12, 95% CI = -0.04, 0.27, P = 0.14; Levine: ß = 0.27, 95% CI = 0.08, 0.45, P = 0.01); however, additional adjustment for current BMI attenuated the associations. Among parous women, a history of abnormal glucose tolerance during pregnancy was associated with increased epigenetic age by the Hannum clock (ß = 0.96; 95% CI = 0.10, 1.81; P = 0.03) and Levine clocks (ß = 1.69; 95% CI = 0.54, 2.84; P < 0.01). In epigenome-wide analysis, increasing parity was associated with methylation differences at 17 CpG sites (Bonferroni corrected P≤ 1.0 × 10-7). LIMITATIONS, REASONS FOR CAUTION: We relied on retrospective recall to ascertain reproductive history and pregnancy complications. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that parity is associated with small increases in epigenetic age and with DNA methylation at multiple sites in the genome. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049033, Z01-ES049032 and Z01-ES044055). None of the authors have a conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.