Gestational weight gain in pregnant women with obesity is associated with cord blood DNA methylation, which partially mediates offspring anthropometrics

Abstract

Gestational weight gain in pregnant women with obesity is associated with cord blood DNA methylation, which partially mediates offspring anthropometrics Dear Editor, Obesity and excessive gestational weight gain (GWG) influence the offspring's future health, and DNA methy-lation, an epigenetic mark occurring on CpG sites, constitutes a potential mechanism underlying this relationship. 1,2 GWG has been associated with birth-weight, fat mass in newborns, and childhood obesity. 1 Additionally, other suggested offspring long-term health effects linked to GWG are cancers and neurodevelop-mental outcomes such as attention-deficit/hyperactivity disorder. 1 To our knowledge, associations between GWG and DNA methylation in cord blood have only been investigated in normal-weight populations using either epigenome-wide association studies (EWAS) 3,4 or a panel of ∼1500 sites 5. In the EWAS of normal-weight women, no associations between GWG and DNA methylation in cord blood were found. 3,4 We, therefore, examined if GWG in women with obesity, with a wide range of GWG (-5.0-34.1kg), associated with cord blood DNA methyla-tion in the offspring of 232 newborns participating in the Treatment of Obese Pregnant Women study using EWAS (Figure S1 and Table 1, see Methods in Supporting Information). Approximately half of the women exceeded, and a quarter either stayed within or gained less weight than the Institute of Medicine recommendations regarding GWG. To test if cord blood DNA methylation is associated with GWG independent of treatment allocation, a linear regression model adjusted for maternal and offspring con-founders and cell-type composition using a reference-free method was used (Model 1, Figure 1A). We additionally examined three models: Model 2, an unadjusted model without cell-type composition adjustment; Model 3, adjusted for maternal and offspring confounders, without cell-type composition adjustment; and Model 4, adjusted for maternal and offspring confounders and cell-type composition using a reference-based method (Figure 1A, see details in Supporting Information, Methods). In This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. TA B L E 1 Parental and offspring baseline characteristics for subjects with available cord blood of the Treatment of Obese Pregnant Women (TOP) study Maternal characteristics n = 208 Maternal age at enrolment (years) † 31.07 (4.45) Pre-pregnancy BMI (kg/m 2) † 34.25 (3.99) Maternal educational level, n (%) ‡ 1. Grammar school 10 years 21 (10.1) 2. Secondary school 12 years 25 (12.0) 3. Vocational training school 19 (9.1) 4. Further education 1-2 years 38 (18.3) 5. Tertiary education 3-4 years (Bachelor level) 75 (36.1) 6. Advanced education (post-graduate) 28 (13.5) 7. NA 2 (1.0) Ethnicity, European, n (%) ‡ 206 (99) Smoking during pregnancy (yes), n (%) ‡ 13 (6.2) Parity (multi), n (%) ‡ 94 (45.2) Gestational weight gain (kg) † 9.68 (6.28) Paternal characteristics n = 180 BMI at enrolment (kg/m 2) † 27.26 (4.50) Offspring characteristics n = 208 Sex, n (%) ‡ Female 100 (48.1) Male 108 (51.9) Gestational age (weeks) † 40.11 (1.26) Birthweight (g) † 3707.64 (492.31) Birth length (cm) † § 52.49 (2.18) Lean mass (%) † ¶ 88.93 (4.47) † Mean (SD). ‡ Frequencies. § n = 200. ¶ n = 139. Abbreviations: NA, not available; BMI, body mass index; SD, standard deviation. model 1, we found GWG to associate with differential DNA methylation at 441 sites, annotated to 352 genes, for example, ABCC8, FOXA2, GATA3, GRB10, NEUROD2, Clin. Transl. Med. 2023;13:e1215. wileyonlinelibrary.com/journal/ctm2 1 of 7 https://doi.