Predictors and Health Consequences of Epigenetic Changes Associated with Excess Body Weight in Women of Child-bearing Age

Background: Epigenetic alterations occurring during pregnancy have recently emerged as important factors for developmental programming of the fetus leading to obesity-related diseases in children. However, the role of excess body weight (EBW) in the modification of epigenetic patterns or its health consequences during child-bearing age is largely unknown. Because a lower degree of DNA methylation of long interspersed nucleotide element-1 (LINE-1) in PBMCs was shown to be associated with a higher risk of developing obesity-related diseases, for example cancer, the purpose of this study was to (1) evaluate the influence of indicators of obesity (BMI, WC, and % body fat) on PBMC LINE-1 methylation, (2) determine the predictors of PBMC LINE-1 methylation, and (3) determine the influence of PBMC LINE-1 methylation on biomarkers of obesity-related diseases.

Methods: The study population consisted of 470 child-bearing age women. We quantified the degree of PBMC LINE-1 methylation by pyrosequencing. Folate concentrations were measured using a microbiological assay. The degree of LINE-1 methylation (> median vs. ≤ median) was the dependent variable in logistic models that specified BMI (>25 vs. ≤ 25), WC (>88 cm vs. ≤ 88 cm), or % body fat (>33% vs. ≤ 33%) separately as the independent predictors of primary interest, adjusting for other relevant variables. The predictors and determinants of lower LINE-1 methylation were evaluated among women with EBW.

Results: Women with higher BMI, WC, or % body fat were 2.0, 1.9, and 1.8 times more likely to have lower LINE-1 methylation, respectively (P = 0.003, 0.005, and 0.01). The predictors and determinants of lower LINE-1 methylation yielded similar patterns with all three indicators of obesity. The following results are based on models run with BMI as the indicator for EBW. Women with higher plasma folate concentrations were less likely to have lower LINE-1 methylation (OR = 0.54, P = 0.0009). Higher LINE-1 methylation was associated with lower insulin resistance as indicated by HOMA (OR = 0.50, P = 0.02).

Conclusions: EBW-associated lower LINE-1 methylation in women of child-bearing age appears to have significant, and potentially transgenerational, health consequences. Higher folate status may exert beneficial effects on obesity-related health outcomes.