presentatie prof. de graaf en dr. willems van dijk

CardiobesityUnravelling the mechanistic link

between obesity, metabolic disorders and cardiovascular disease

Jacqueline de Graaf Ko Willems van Dijk

CardiobesityConsortium

Name Institute Genetics Clinical pheno-typing

In vitro analysis

Animalmodel

SystemsBiology

CohortsIntervention

Prof. C. van Duijn ErasmusMC X X

Prof. J. de Graaf UMCN X X X

Dr. K. Willems van Dijk

LUMC X X

Prof. M. Hofker UMCG X X X X

Prof. E. Feskens WUR X X X

Prof. P. Slagboom LUMC X X

Prof. C. Stehouwer MUMC X X

Dr. B. van Ommen TNO X

Prof. T. Hankemeier UL X

Is it possible to identify those overweight

individuals who are prone to developing

cardiovascular disease?

CardiobesityHealth care problem

AgeGender

Mechanisms

Obesity

Metabolic disorders CVD

We will reveal novel genes and

markers for improved risk stratification,

personalized prevention, and new

therapeutic options to decrease the CVD

burden in the overweight

CardiobesityResearch questions

What markers/parameters identify those overweight subjects at increased risk for metabolic

disorders and CVDWP 6 Genomics platforms and system biology

What molecular mechanisms, especially in adipose tissue, are responsible for increased

risk for metabolic disorders and CVD?

WP1Genetics

WP2Clinical phenotype

WP 4Molecular mechanisms

WP3Adipose tissue functionality

WP 5 Cohorts / Intervention trials

Novel candidate genes and markers for CV risk stratification and personalized prevention in overweight individuals

Familial Combined HyperlipidemiaN=687 – 70 familiesOverweightMetabolic DisordersPremature CVD

WP1: GeneticsWhole exome sequencing

WP3: Adipose tissue characterizationIn vitro analyses

WP6: Genomics analysis platformsTranscriptomics, metabolomics, proteomics

WP2: Obesity and vascular imagingIn depth clinical phenotyping

Candidate mechanisms linking obesity with CVD

WP6: Systems BiologyData integration and interpretation

WP4:Mouse modelsMechanistic studies

Leiden Longevity CohortN=3500 – 420 familiesMetabolic healthCVD protection

Large cohortsSelection of overweight subjects- with/without CVD- with and without metabolic disorders

WP5: EpidemiologyValidation in large cohorts

N>75.000and by interventions

Novel genes and markers for CV risk stratification and personalized prevention in overweight individuals














Leiden Longevity Cohort

Aging cohort with low cardiometabolic risk

420 families – 3500 subjects

Available data:

GWAS (n=3500)

Sequence data (n=220)

Metabolomics (n=3500)














Whole exome sequencing

Reference data bases:

• 1000 genome projects• 250 trios in GoNL

• ERF study (n=3000)• GWAS• exome sequencing• metabolomics














CT, MRI, DEXA

Obesity-imaging

Nail fold capillaroscopy

Retinography

Endothelial Glycocalyx

Micro-vascular imaging

IMT, PWV, ABI, Plaques

MRI, PET/CT, CEUS

for vulnerable plaques

Macro-Vascular imaging














Adipose tissue biopsiesEx vivo and in vitro

InflammasomeNod like receptorsImmune cellsTranscriptomicsMetabolomicsProteomics














Integrated data warehousing

Bioinformatics and biostatistics

System biology














Nijmegen Biomedical StudyN=1517

ERF and Rotterdam studyN=3000 and n=12.000

Maastricht study and CODAMN= 6000 and n=574

LifeLines n>50.000

Leiden Longevity Study Trial n=60

EetMeetWeetN=300














CardiobesityTranslation axis

Patients: FCH, LLS, cohort subsets

Basic and translational researchGeneticsClinical phenotypingSystems biologyAdipose tissue studiesMouse models

Candidate mechanisms: Linking obesity and CVD

Epidemiology: Cohorts and interventions

Novel candidate genes and markers for CVD risk stratification and personalized prevention in overweight individuals

Focus areas Dutch

Heart Foundation:

Aging Gender

Metabolic disorders

CardiobesityFocus areas

Obesity


AgeGender

Mechanisms

Cardiobesity consortiumUnique in combining expertise in basic,

clinical and epidemiological research resulting in integrated approach to link obesity to CVD

Cardiobesity(Inter)national perspectives

Collaboration with (inter)national consortia:

‘Complementary and confirmatory replication’

GoNL – BBMRI – NCHA – CHANCES – IDEAL – EAGLE EPI2 - CTMM ‘predict’ - NCSB – CMSB2 – NMC

To identify those

overweight individuals who

are prone to develop

cardiovascular disease by

revealing the mechanisms

linking obesity to CVD

Cardiobesity

AgeGender

Mechanisms

Obesity


presentatie prof. de graaf en dr. willems van dijk

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