Genes, Molecular Mechanisms and Risk Prediction for Abdominal Aortic Aneurysm

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1 Genes, Molecular Mechanisms and Risk Prediction for Abdominal Aortic Aneurysm Arne IJpma Clinical Genetics Department, Erasmus MC, Rotterdam, The Netherlands

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

3 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

4 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

5 Study Population Dutch population 595 AAA index patients 182 (30%) familial index cases (faaa) 413 sporadic cases Extensive clinical (echo) workup for ~300 families

6 Risk Factors For faaa Index AAA patients <65 years at diagnosis, without diabetes mellitus and without hypertension have 4 fold higher risk of faaa

7 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

8 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

9 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

10 AAA Gene Expression Analysis

11 Risk factors for AAA & Atherosclerosis

12 AAA Gene Expression Analysis Patient Groups Characteristics

13 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

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

15 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

16 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