Genetics and Systems Biology of the Metabolic Syndrome

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. We participate in the LUMC research themes Cardiovascular, Medical Genomics and Lifecourse. Our research is focused on the pathology of the metabolic syndrome with emphasis on the relation between obesity, dyslipidemia, type-2 diabetes and cardiovascular disease.

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 cardiovascular disease are also increasing dramatically.

We address the pathology of the metabolic syndrome using a systems biology based approach encompassing in depth characterization of patients and controls using a variety of state-of-art clinical and -omics approaches. We study well-defined patients which have undergone very specific interventions (i.e. bariatric surgery or timed caloric restriction) and determine the effects of these interventions on plasma and tissue specific markers using -omics tools (i.e. metabolomics, transcriptomics, proteomics). Systems biology based on mathematical and statistical modelling are applied to combine and interpret the data. The same -omics and modelling tools are used in large cohorts to determine the associations of specific markers or pathways with present or future disease. Causal associations are furthermore assessed using Mendelian Randomization analyses. For these aspects, we have full access to the Netherlands Epidemiology of Obesity (NEO) study, hosted at the LUMC. In addition, we have access to the UK biobank (N=500.000) which comprises a plethora of –omics and clinical data and collaborate in large international consortia (i.e. CHARGE). These large cohorts and collaborative consortia also provide us with the statistical power to assess the role of gene-gene and gene-environment interactions.

The embedding of the research in both Human Genetics and Internal Medicine / Endocrinology allows for swift transition of bench-to-bedside and bedside-to-bench research. Where possible, we collaborate closely with colleagues to further assess underlying mechanisms, but also to assess potential therapeutic approaches in vitro and in vivo using mouse models. This 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 exploited to discover the role and mechanism of novel findings and also to assess therapeutic potential.

Our Team Ko A.P. Willems van Dijk         
Principal Investigator / Professor Genetics and Systems Biology of the Metabolic Syndrome

Jan Bert van Klinken       

Linjun Ao           
PhD student

Wenyi Wang     
PhD student