The role of epigenetics in gestational diabetes

Project title
Genome-wide gene expression in black South African women who develop Gestational Diabetes Mellitus (GDM)

Research question
To understand the impact of gestational diabetes on the developing fetus by investigating gene expression and DNA methylation of genes that may be involved in the development of the disease. This will allow us to identify epigenetic perturbations that may lead to an unfavourable outcome in the offspring.

Rationale
Diabetes mellitus is a metabolic disorder in which the body fails to either produce insulin (Type 1) or utilise insulin correctly (Type 2), resulting in the characteristic high blood glucose levels observed in affected individuals.  Insulin, a hormone produced by the beta cells of the pancreas, is responsible for the activation of the process of blood glucose conversion into energy within the cells. Diabetes affects almost every population in the world and is a large, growing, and costly public health problem.  When pregnant women exhibit high blood glucose levels first observed during pregnancy, it is referred to as gestational diabetes mellitus (GDM). GDM is associated with short and long term morbidity in both the mother and the offspring and is predictive for poor pregnancy outcomes.  The development of GDM predisposes the mother to a higher risk of developing Type 2 diabetes (T2D) later in life and increases the foetuses risk of developing adult onset diseases such as diabetes, obesity and cardiovascular disease. Many epidemiological studies have demonstrated that an adverse intrauterine environment may play a critical role in determining the foetuses susceptibility to chronic diseases. A developing fetus exposed to an adverse intrauterine environment will need to adapt to ensure its survival. These adaptions are thought to act through epigenetic modifications such as DNA methylation, histone modification and non-coding RNAs. These epigenetic changes are established early on in life and control the expression of certain genes during development.

Sample collection for this study was done in collaboration with the Foetal/Soweto baby growth study which aims to recruit over 4000 participants for their study. The target population was black South African women in their first trimester of pregnancy who present at clinics around the Soweto, Johannesburg area. All participants were required to provide written informed consent. At 24-26 weeks gestation, each participant had an oral glucose tolerance test (OGTT) done to assess their glucose tolerance levels during pregnancy. IADPSG criteria for the diagnosis of GDM was used.  It is from this larger cohort of patients that subjects (N=12; 6 GDM cases and 6 healthy controls) for this project were selected. Venous blood samples were obtained from these selected women. At the time of delivery, placental tissue biopsies were obtained from each of the selected women’s newborn. The anthropometric data (such as weight, length and head circumference) was taken. RNA and DNA were extracted from the blood and placental samples. After quality control was done, RNA –sequencing was performed using the RNA samples and the Hiseq 2000 Illumina sequencing machine. In depth analysis of the gene expression data obtained from RNA sequencing was analyzed and candidate genes with significant differential expression were identified. These results were validated using qRT-PCR methods. The DNA methylation around the promoter region of these genes will be analyzed to identify if an aberrant promoter methylation pattern is responsible for the change in gene expression in GDM women compared to controls. The gene expression and DNA methylation pattern of these genes will be studied in the placenta to understand the impact of GDM environment on the developing fetus.

Research output
Hobbs, A and Ramsay M (2015) epigenetics and the burden of noncommunicable disease: a paucity of research in Africa. Epigenomics 7(4) 627-639

Supervisors
Professor Michele Ramsay; Professor Shane Norris