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 r ² 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.

Abstract

Karen Lillycrop and colleagues investigate whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.

Author summary

Why was this study done?

• The incidence of gestational diabetes is increasing worldwide, concurrent with a rise in obesity with children born to mothers with gestational diabetes mellitus (GDM) having a heightened risk of obesity and metabolic disease, perpetuating an intergenerational cycle of metabolic disease.

• High circulating levels of glucose in mothers with GDM have been suggested to trigger epigenetic changes (chemical modifications that affect gene activity and the amount of protein produced from them) during development of the fetus, resulting in an increased susceptibility to metabolic disease in later life.

• As little is known of the epigenetic changes induced by maternal GDM within mothers with obesity, a high-risk population for GDM, we examined relationships between DNA methylation in infants born to mothers with obesity who developed GDM and those who did not and the mother’s blood glucose concentration. We then examined whether a dietary and physical activity intervention during pregnancy, designed to improve maternal glycaemia, modified the DNA methylation changes in the infant associated with maternal GDM exposure.

What did the researchers do and find?

• Using samples from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT) of lifestyle intervention (low glycaemic index (GI) diet plus physical activity) versus standard care in pregnant women with obesity, we investigated cord blood DNA methylation levels from 557 newborn infants.

• Maternal GDM status and high circulating maternal glucose levels were associated with modest changes in DNA methylation in the infants.

• The methylation changes observed in the infant associated with maternal GDM exposure appeared to be reduced by the pregnancy lifestyle intervention.

What do these findings mean?

• These findings suggest that the impact of high maternal circulating glucose levels on DNA methylation in the infant can be modified by a lifestyle intervention in pregnancy.

• Follow-up studies are needed to establish whether the reduction in DNA methylation changes observed in infants from mothers with GDM undertaking the lifestyle intervention is accompanied by improved health outcomes of the children in later life.