Functional Genomics of Systemic Disorders

The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Human Genetics.

Aim and focus

The common focus of this program is to apply functional in vitro, in vivo as well as genome wide studies to uncover and resolve the mechanisms underlying systemic disorders such as metabolic syndrome, type 2 diabetes, cardiovascular disease and kidney failure. The aim of this multidisciplinary, state-of-the art program is to understand and to translate the insights gained into mechanisms and pathophysiology of these complex multifactorial diseases towards the development of improved prediction, prevention, new drug targets and potential therapies. Therefore, our research covers a broad range of topics such as genotype-phenotype studies, modifying genes, studies on expression and functions of the genes/proteins involved, cellular signalling and bioinformatics, pathogenesis, organoid culturing, drug screening and preclinical testing.

Based on a strong background in monogenic extremes of systemic disorders (including ApoE3-Leiden mutations in familial hyperlipidemia and PKD1 and PKD2 mutations in polycystic kidney disease), this program also aims to utilise the knowledge gained from these monogenic disorders in our studies to common and multifactorial forms.  
Therefore, complex gene-gene and gene-environment interactions are investigated using the full spectrum of genome wide technologies and mathematical systems biology approaches on prospective epidemiological cohorts that are available in-house (Netherlands Epidemiology of Obesity study) or in close collaboration (Doetinchem study, RIVM; Erasmus Rucphen Family Study, Erasmus University Rotterdam; PKD-DIPAK-consortium; PKD-Modifier consortium, Mayo-clinic).  
In addition, targeted analyses as well as high-throughput drug screening using organoids are among the approaches to identify potential therapeutic targets. These are multidisciplinary programs in collaboration with bioinformaticians, chemo-informaticians, clinicians and toxicologists
One of the common mechanisms studied, involves antibody effector pathways in chronic inflammation in immune diseases. These are also important in autoimmune diseases such as arthritis and SLE. Advanced novel mouse models have been and are being generated for functional analysis of FcR and complement.

Position in international context

The department has a strong history of lipid genetics and kidney disease research. Our mouse model research has amongst others yielded the ApoE3 Leiden mouse, a worldwide standard model for human-like lipid metabolism, and a panel of mouse models for PKD, currently being used in therapy studies (in private-public partnership). A state-of-the-art facility has been established to generate site specific and conditional mouse mutants, successfully using for example CRISP/Cas9 technology.  Together with the NKI a bi-annual international workshop is organized to discuss the most recent advances in genome engineering technology.
With the unique panel of conditional KO mice deficient for different combinations of Fc receptors of IgG, an international network of collaborations has been established to address the role of IgG in (chronic) inflammations, autoimmune diseases and in cancer therapy.
Our work yields papers in high quality journals, invitations for international conferences, and international awards. Our research is funded by national and international (consortium) grants like EU, PKD Foundation, Dutch Kidney Foundation, Dutch Heart Foundation, and the Diabetes Fund, as well as by national funding instruments from NWO and STW. The department coordinates several (inter)national consortia.

Content / highlights / achievements

  • Identified common genetic variation associated with risk factors for metabolic syndrome and associated pathology (published in Nature Communications, PLoS Genetics, Diabetes).
  • Functional insight in the development of metabolic syndrome and associated pathology in mouse models (developed a fully operational 'mouse metabolic clinic').
  • Functional insights in PKD from unique mouse models and from in house generated CRISPR/Cas9 induced PKD1-/- iPSCs.
  • A unique collection of immune-deficient mouse strains (including a FcgR quadruple KO deficient for all FcgR and cell type specific FcgR KO strains) has been constructed in the field of antibody dependent inflammation, which has opened great opportunities to collaborate with international companies.
  • Automated workflows for metabolic pathway analyses. In addition to enabling biological interpretation of results, these workflows were used as substrate for developing better documentation practices for bioinformatics-based research.
  • High-throughput drug screenings for PKD in collaboration with SME OcellO.
  • Peters: Coordinator of a EU-FP7 MCA Initial Training Network on Translational research (training) in Polycystic Kidney Disease ('TranCYST', 2012-2016). Project leader of the STW consortium  'A screening platform for the identification of effective therapies for Polycystic Kidney Disease'.  Coordinator of the Dutch consortium 'Developing Intervention strategies to halt Progression of Autosomal Dominant Polycystic Kidney Disease' (DIPAK). 
  • Verbeek: Coordinator of a EU-FP7 MCA Initial Training Network 'TIMCC' with six academic and two private sector partners, focusing on the Tumor Infiltrating Myeloid Cell compartment (2012-2016). 
  • Willems van Dijk: PI and work package leader in two Cardiovascular Research Netherlands programs:  CVON-In-Control (2013-2018) 'The role of the gut microbiota and chronic inflammation as drivers of cardiovascular disease and CVON-Energise (2015-2019) 'targeting energy metabolism to combat cardiovascular disease'. 
  • Industrial collaborations with Unilever, Galapos, Innoser, Alligator, Mosaiques, Baxter, OcellO, Ipsen Pharmaceuticals, SPECS.

Future themes

  • To gain insight into the mutation spectrum and the identification of modifying genes for PKD by state-of-the-art NGS technologies. DNA-diagnostics is performed at the diagnostic service of the department of Clinical Genetics (LDGA). Studies will include the patient cohort collected and characterized as part of the Dutch DIPAK-consortium (Developing Intervention strategies to halt Progression of Autosomal Dominant Polycystic Kidney Disease).
  • To develop functional assays to predict the pathogenicity of missense variants in PKD. An integration and validation of new prediction tools and molecular assays in collaboration with bioinformaticians and the department of Clinical Genetics (LDGA).
  • To identify and validate new tools to predict and monitor disease progression and to assess early treatment effects, metabolomic/proteomic profiling approaches will be used in mouse models and compared to patients with PKD.
  • In-depth analysis of genetic and epigenetic alterations in PKD in combination with analysis of signal transduction pathways.
  • Application of bioinformatics and biosemantics approaches to predict biological relations.
  • Identifying new drug targets and test new treatment strategies for PKD. Both, screening approaches and targeted approaches will be applied. Preclinical drug testing will be done in mouse models and organoids. National and international collaborations exist.
  • Detailed analysis of cardio-vascular abnormalities and renal vasculature.
  • The role of tissue-specific inflammation in the development of the pathology associated with the metabolic syndrome.
  • The role of gut microbiota in the development of the pathology associated with the metabolic syndrome and the role of gut-derived metabolites and (tissue-specific) inflammation as underlying mechanisms.
  • The application of mathematical systems biology to gain quantitative insight in the role of common genetic variation in metabolite patterns, gene expression signatures and the development of pathology associated with the metabolic syndrome.
  • The genetics of trajectories of clinical and metabolomic(s) parameters using the Doetinchem cohort (RIVM, Dollé) with 30 years of follow-up.
  • The development of a cross-discipline systems approach that combines mathematical systems biology, semantic networks and data integration to provide insight into the mechanisms governing the pathology associated with metabolic syndrome.
  • To exploit the latest technical possibilities (modified BAC transgenics, TALENs and CRISPR/Cas9 induced mutations etc.) to develop disease-related cell models and to develop mouse models. (Conditional) FcR and complement factor/receptor-deficient mice have been generated on the well-defined C57Bl6 background. This will enable a detailed analysis of the cell type-specific role of these molecules in protective immunity and inflammatory diseases such as arthritis, nephritis and SLE.

Cohesion within LUMC

Studies on the Metabolic Syndrome, cardiovascular disease and type 2 diabetes are performed in close collaboration with the department of Internal Medicine, Endocrinology, Clinical Epidemiology (NEO cohort) and are part of the Einthoven laboratory for Experimental Vascular Medicine. Studies into the mutation spectrum for PKD and the identification of modifying genes are performed in close collaboration with the department of Clinical Genetics; clinical studies and biomarker studies of PKD in collaboration with Nephrology and the Center for Biomolecular Mass Spectrometry; the molecular Pathology of PKD and signal transduction studies with Pathology and Mol Cell Biology. Culturing of organoids and iPSCs in collaboration with Nephrology and Anatomy & Embryology (IPSC core facility). Preclinical drug screening is performed with the Leiden Academic Centre for Drug Research and OcellO. Multidisciplinary integration of expression profiles, identified compounds; drug target predictions are performed with bio-/chemo-informaticians (human genetics and LACDR). Fruitful collaboration with the departments of Immunohematology, Internal medicine and Rheumatology resulted in joint national and international grants.