Methylomics of prenatal GDM: Natural history & lifestyle intervention in children

The number of pregnancies complicated by Gestational Diabetes Mellitus (GDM) has risen worldwide in recent years. GDM is now diagnosed in as many as 7% of all pregnancies in the US.1 In Tianjin, China, GDM rates have reached 8.2% in 2012, similar to the US level.2 Children of GDM mothers are larger in size and show ~20% more adiposity at birth than non-GDM children, are ~100% more likely to develop overweight or obesity during childhood,3,4 and exhibit 1-6 fold higher risk of obesity, impaired glucose tolerance, and type 2 diabetes as young adults.3,4 In our recent work in Tianjin, a lifestyle intervention in children of GDM mothers has produced prompt benefits on body weight, body mass index (BMI), plasma lipids, and waist and chest circumferences compared to usual care.5 Yet, lifestyle interventions are not ultimately successful in all children, as ~75% of them lose all or part of the benefit or even rebound over time.6 We currently have no means to predict who will have long-term benefit after a lifestyle intervention. Biomarkers to monitor active interventions and accurately predict their success would be a vital tool to develop new strategies to personalized prevention. Epigenetics may provide a tremendous opportunity to address this critical public health gap. Landmark findings from the Dutch Famine study revealed that alterations of maternal metabolism during pregnancy produce changes in offspring DNA methylation – an epigenetic mark of gene programming – detectable in blood of obese individuals even decades after birth.7-9 Because the epigenome is established in utero and can be shaped by both prenatal and postnatal exposures, DNA methylation holds considerable promise to develop biomarkers of prenatal GDM exposure, future cardiometabolic risk and effectiveness of lifestyle interventions. Our long-term goal is to identify easy-to-measure blood-based biomarkers of prenatal GDM exposure, cardiometabolic risk of GDM-exposed children, and probability of success of a standard lifestyle intervention. We have a unique opportunity to achieve this goal because we can leverage a wealth of resources from two inter-related studies, the Tianjin GDM Observational study (TGDM-O) and the lifestyle-intervention Trial (TGDM-T). TGDM-O is a 5-year longitudinal study of children with or without prenatal GDM exposure.5 TGDM-T is a randomized controlled trial including a 3-year early-childhood lifestyle intervention and 2-year post-intervention follow-up.5 The longitudinal design of TGDM-O and TGDM-T, and ready-to-use collections of biospecimens, anthropometry and lab cardio-metabolic data provide a tremendous time- and cost-effective opportunity to characterize methylomics both as part of the child natural history and after a lifestyle intervention.