Precision medicine is the future path in many different clinical areas. We also pursue research into hereditary obesity, skeletal disorders and hereditary hearing loss. Please read below for a brief overview of these research areas.
Background
Obesity is a major health risk with increasing prevalence. It is associated with fat accumulation in adipose tissue and also ectopically in tissues such as the liver and skeletal muscle. Ectopic fat accumulation in the liver (non-alcoholic fatty liver disease, NAFLD) may be associated with chronic liver necroinflammation (non-alcoholic steatohepatitis, NASH). It has become clear that NAFLD/NASH is not only a consequence of obesity, but also a driving force behind both metabolic and cardiovascular problems.
The mechanisms and processes underlying the development of obesity are undoubtedly multifactorial in nature. First, numerous studies have shown that 40-70% of inter-individual variability in BMI can be attributed to genetic factors. Given the estimated heritability, extensive genome-wide association studies (GWASs) have been conducted to identify common single nucleotide polymorphisms (SNPs) that may underlie the hereditary risk of human obesity. Despite the fact that a large number of associated variants were identified, they explain only a small percentage of the genetic variability. Second, the dramatically increasing prevalence cannot be explained solely by genetic factors. The same applies to NAFLD/NASH, for which several SNPs have been identified that, as background modifiers, explain some of the inter-individual variation in the presence and severity of these liver pathologies.
Goal
The aim of the study is to study the effect of genetic variants on the risk of obesity and to investigate their contribution to the development and progression of NAFLD/NASH.
Strategy
Thanks to long-standing clinical collaborations, samples from large cohorts of patients are available for study. A multi-omics approach, including genomics, epigenomics and transcriptomics, is used to identify and characterize genetic variants that may contribute to the pathogenesis of obesity and associated liver diseases. In addition, in vitro functional studies are being conducted and zebrafish models are being created to validate variants of potential interest.
Background
Osteoporosis is the most common metabolic bone disease, characterized by reduced bone mass resulting in an increased risk of fractures. It is a multifactorial disease in which environmental factors contribute, but heritability is also high, indicating an important role for genetic factors. Over the past decade, many new genes and associated pathogenic mechanisms have been identified by studying monogenic disorders involving abnormal bone mass. This includes the sclerosing bone dysplasias in which patients have increased bone mass.
Goal
We aim to identify novel genes and genetic variants that are causal for increased bone mass in monogenic sclerosing bone dysplasias. Unraveling these pathogenic mechanisms is relevant for patients, but may also lead to insights into bone mass homeostasis in the general population and in patients diagnosed with osteoporosis.
Strategy
DNA sequencing is performed on DNA from patients with abnormal bone mass. The approach can vary from sequencing candidate genes, using a (virtual) gene panel or sequencing the entire exome or genome. Genetic variants of potential interest are validated by in vitro functional studies or by construction and phenotyping of animal models, including mouse and zebrafish models.
Within research into hereditary hearing loss, research is being conducted into the biological function of the DFNA5 gene. This gene appears not only to be responsible for hereditary deafness, but also to play an important role in the development of frequent forms of tumors, such as breast and intestinal tumors. In collaboration with the oncology department of the University of Antwerp, a project has been started on the role of DFNA5 in frequent solid tumors. This collaboration has grown into a larger line of research, in which oncogenetic research is conducted into various forms of cancer, such as pancreatic neuroendocrine tumors, mesothelioma and breast cancer. It was recently published that DFNA5 offers excellent prospects as a biomarker for breast cancer and colorectal cancer.
In addition to the role of DFNA5 in hearing loss, our research group is also studying complex forms of hearing loss. These are forms of hearing loss due to a complex interplay between multiple genes and environmental risk factors. The focus lies on age-related hearing impairment (ARHI) and otosclerosis, a form of hearing loss characterized by fixation of the stapes. For both condition, large sample sets have been collected through international collaborations. Over the years, we have repeatedly applied the state-of-the-art techniques of sequencing and data analysis to elucidate which genetic variants, metabolic pathways and biological processes are involved in the pathophysiology.
