Genes, Molecular Mechanisms and Risk Prediction for Abdominal Aortic Aneurysm

Klinische Genetica Vooraanstaand in erfelijkheidsvraagstukken

Genes, Molecular Mechanisms and Risk Prediction for Abdominal Aortic Aneurysm

Arne IJpma Clinical Genetics Department, Erasmus MC, Rotterdam, The Netherlands


Financial Disclosure

I have no financial relationships to disclose This work is supported by a grant from the Lijf and Leven Foundation


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


AAA Study Workflow Collaboration between Clinical Genetics, Vascular Surgery and Genetics Clinical work up of patients

Patient surgery/ tissue collection

• Analysis of risk factors NGS sequencing of index and affected relatives

Microarray analysis

• Sequence variant analysis

• RNA expression analysis of AAA tissue

• Functional validation studies


Study Population

• Dutch population • 595 AAA index patients • 182 (30%) familial index cases (fAAA) • 413 sporadic cases • Extensive clinical (echo) workup for ~300 families


Risk Factors For fAAA

Index AAA patients <65 years at diagnosis, without diabetes mellitus and without hypertension have 4 fold higher risk of fAAA


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


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


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


AAA Gene Expression Analysis


Risk factors for AAA & Atherosclerosis


AAA Gene Expression Analysis Patient Groups Characteristics


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


AAA Gene Expression Analysis

Top 5 up-regulated genes

COL11A1 expressed in ECM ADIPOQ is elevated in Kawasaki patients (aneurysms in coronary artery)


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


Acknowledgements – AAA Study Group Clinical Genetics:

Danielle Majoor-Krakauer Daphne Heijsman Michael Oomen Isabel Abazie

Vascular Surgery:

Koen van de Luijtgaarden Ellen Rouwet Sander ten Raa Hence Verhagen

Genetics:

Luuk te Riet Ingrid van der Pluijm Jeroen Essers

Genes, Molecular Mechanisms and Risk Prediction for Abdominal Aortic Aneurysm

Recommend Documents