Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Arne IJpma
Clinical Genetics Department, Erasmus MC, Rotterdam,
The Netherlands

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Financial Disclosure
I have no financial relationships to disclose
This work is supported by a grant from the Lijf and Leven Foundation

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Study Approval
• This study is approved by the METC of Erasmus MC,
Rotterdam, The Netherlands
• All patients in our study have given informed consent
• All patient tissue handling is done according to strict protocols as approved by the METC

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Study Workflow
Collaboration between Clinical Genetics, Vascular Surgery and Genetics
Clinical work up of patients
NGS sequencing of index and affected relatives
• Analysis of risk factors
• Sequence variant analysis
Patient surgery/ tissue collection
Microarray analysis
• RNA expression analysis of AAA tissue
• Functional validation studies

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Study Population
• Dutch population
• 595 AAA index patients
• 182 (30%) familial index cases (fAAA)
• 413 sporadic cases
• Extensive clinical (echo) workup for ~300 families

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Risk Factors For fAAA
Index AAA patients <65 years at diagnosis, without diabetes mellitus and without hypertension have 4 fold higher risk of fAAA

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Familial AAA: Risk of AAA in First Degree Relatives
• In fAAA, 3-4 fold increased risk for affected siblings as compared to the population risk
• Genetic risk for AAA justifies screening in first degree relatives regardless of gender
• Relatives of affected women show at least similar risk as relatives of affected men

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Candidate Gene Identification
• In process of exome/whole genome sequencing:
 35 fAAA families
 147 single fAAA index patients
 413 sporadic cases
• fAAA inheritance pattern suggests dominant model

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Candidate Gene Identification
• For one family, 5 affected family members were sequenced and all shared one likely pathogenic variant in a TGF beta signaling associated gene
• Linkage and haplotype analysis confirms shared haplotype region containing this gene
• Wetlab validation experiments are ongoing

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Gene Expression Analysis

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Risk factors for AAA & Atherosclerosis

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Gene Expression Analysis
Patient Groups Characteristics

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Gene Expression Analysis
TGF-Beta signaling pathway with overlay of AAA gene expression data
• Many genes in TGF beta pathway are overexpressed in AAA
• TGF beta pathway is predicted to be activated

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
AAA Gene Expression Analysis
Top 5 up-regulated genes
COL11A1 expressed in ECM
ADIPOQ is elevated in Kawasaki patients (aneurysms in coronary artery)

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Conclusions
• 30% of all AAA cases are familial AAA
• Screening relatives of male and female patients is important
• Whole genome analysis approach was successful in identifying a novel candidate gene for familial AAA (TGF beta signaling associated gene)
• Gene expression profiling approach identified
 Pathways (TGF beta signaling) associated with aneurysms
 Genes (COL11A1 and ADIPOQ) with significance to AAA

Klinische Genetica
Vooraanstaand in erfelijkheidsvraagstukken
Acknowledgements – AAA Study Group
Clinical Genetics:
Vascular Surgery:
Genetics:
Danielle Majoor-Krakauer
Daphne Heijsman
Michael Oomen
Isabel Abazie
Koen van de Luijtgaarden
Ellen Rouwet
Sander ten Raa
Hence Verhagen
Luuk te Riet
Ingrid van der Pluijm
Jeroen Essers