Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial

Abstract

Background Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks’ gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. Methods and findings We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant’s cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders. Conclusions Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings. Trial registration ISRCTN89971375.

Epigenetic Changes in Gestational Diabetes Mellitus

“…Cg03566881, a site located within the leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6), had the most significant correlation with GDM. Furthermore, the 1 h glucose level and GDM-associated methylation signatures in the cord blood of offspring appeared to be weakened by the physical activity and dietary intervention during pregnancy [ 66 ]. Similar findings were reported in a study of Haertle et al that compared genome-wide methylation patterns of fetal cord blood from healthy pregnant women and GDM patients.…”

The Impact of Lifestyle, Diet and Physical Activity on Epigenetic Changes in the Offspring—A Systematic Review

“…Among the 16 studies included, 5 studies were RCTs [ 17 , 18 , 19 , 20 , 21 , 26 ] and 11 studies were cohort studies [ 3 , 4 , 6 , 12 , 13 , 14 , 16 , 22 , 23 , 24 , 25 ]. In total, 3617 mother–offspring pairs were included.…”

“…In total, 3617 mother–offspring pairs were included. Seven studies included participants from the USA [ 3 , 4 , 6 ], two from the United Kingdom (UK) [ 14 , 17 ], two from Ireland [ 18 , 19 ] and the rest of the studies included participants from China [ 24 ], Japan [ 16 ], Argentina [ 20 ], Denmark [ 21 ] and Scotland [ 13 ]. Two studies included data from the same RCT that investigated epigenetic changes at birth and at 5 years of age in offspring of mothers on a low glycemic index diet (Geraghty et al [ 19 ] and Geraghty et al [ 18 ], respectively).…”

“…Some of the included studies investigated a lifestyle with a combination of diet and physical activity, while others investigated either a specific diet or dietary components. Four studies investigated physical activity as the exposure variable [ 4 , 6 , 17 , 21 ], four studies investigated carbohydrate intake [ 12 , 14 , 16 , 22 ], four studies investigated glycemic index [ 17 , 18 , 19 , 24 ], two studies investigated sugar intake [ 12 , 23 ], two studies investigated Mediterranean diet [ 21 , 25 ], four studies investigated fat intake [ 12 , 17 , 22 , 27 ] and three studied other exposures (olive oil [ 20 ], unbalanced diet [ 13 ] and pro-inflammatory diet [ 3 ]). Most studies investigated epigenetic changes in the offspring at birth.…”

Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

“…Such changes are not only detectable in adult mice ( 42 ), but also in human fetal umbilical cord blood ( 44 ). In addition, there are multiple reports of modified DNA methylation on sites of importance for metabolic processes after dysglycemia and/or high-fat diet during pregnancy ( 45 – 47 ).…”