Genetics and Systems Biology of the Metabolic Syndrome

Principal investigator
Prof.dr. Ko Willems van Dijk

The metabolic syndrome research within the department of Human Genetics is embedded in the LUMC profile area Vascular and Regenerative Medicine and the Einthoven laboratory for experimental vascular medicine. Our research is focused on the pathology of the metabolic syndrome with emphasis on the relation between obesity, dyslipidemia, type-2 diabetes and atherosclerosis. The metabolic syndrome is defined by the co-occurrence of risk factors for diabetes and atherosclerosis and comprises central obesity, high fasting glucose, high blood pressure, low HDL-cholesterol and high triglycerides. With the ever increasing rate of obesity in Western societies, the rates of type-2 diabetes and atherosclerosis are in parallel increasing dramatically.

The genetics and pathology of the metabolic syndrome are addressed using a systems biology based approach encompassing a combination of in depth characterization of patients and controls and mechanistic research in mouse models. The embedding of the research in both Human Genetics and Endocrinology allows for swift transition of bench-to-bedside and bedside-to-bench research. We study well-defined patients which have undergone very specific interventions (i.e. bariatric surgery or prolonged caloric restriction) and determine the effects on plasma and tissue specific markers using state-of-art –omics tools (i.e. metabolomics, transcriptomics, proteomics). Systems biology based on mathematical and statistical modelling approaches are applied to combine and interpret the data. The same -omics and modelling tools are used in larger cohorts to determine the epidemiological associations of these markers. For this aspect, we have full access to the Netherlands Epidemiology of Obesity (NEO) study, hosted at the LUMC, and we are closely collaborating with the department of Epidemiology of the Erasmus Medical Center in Rotterdam.

The functional genetics approach makes use of the transgenic APOE3Leiden mouse, which, in contrast to wild type mice, displays a human-like plasma lipid profile and is sensitive to diet-induced hyperlipidemia, obesity and insulin resistance as well as premature atherosclerosis. This sensitized phenotype is used to discover the role and mechanism of novel genetic findings.

Animal models
The main goal of the animal models research line is to understand the interplay between lipoprotein metabolism and glucose metabolism in relation to hyperlipidemia and insulin resistance. An extensive set of animal models is available for this purpose, selected to address specific aspects of these interactions. In addition, extensive know-how, technology and equipment is available for in vivo  characterization of lipid and lipoprotein metabolism, glucose metabolism (insulin sensitivity), energy metabolism and atherosclerosis. These models are exquisitely suited to address the molecular mechanisms of disease, but also serve as pre-clinical models for the analysis of the efficacy of therapeutic intervention.