Abstract 17051: Genome-wide Copy Number Analysis Identifies New Candidate Genes for Thoracic Aortic Aneurysms and Dissections
Purpose: Aortic aneurysms and dissections are the nineteenth leading cause of death in the United States. The spectrum of thoracic aortic aneurysms and dissections (TAAD) ranges from congenital disorders to sporadic isolated disease of unknown cause. We hypothesized that genomic copy number variants (CNVs) contribute causally to sporadic TAAD (STAAD).
Methods: We conducted a genome-wide SNP array analysis of STAAD patients of European descent who underwent treatment at Baylor College of Medicine (BCM group). Genotyping was performed on the Illumina CNV370 platform. We used PennCNV and CNVPartition for in silico detection of CNVs. 418 STAAD patients were compared to 5,088 dbGAP controls without a history of vascular disease. Thresholds were set at a minimum of five consecutive SNPs for CNVs that were identified by both algorithms and intersect with known genes. For replication, 387 STAAD patients from the University of Texas Health Science Center (UTHSC group) and 88 probands from families with at least two affected relatives (FTAAD group) were screened for additional CNVs at these loci with SNP arrays.
Results: We identified six recurrent CNVs in the BCM group that were absent or extremely rare (frequency <0.1%) in 5,088 controls. Twelve rare CNVs that were either very large (>2 Mb) or shared by BCM and UTHSC or FTAAD patients were also identified. Seven rare CNVs involved genes that cause arterial aneurysms when mutated. The largest and most prevalent of the recurrent CNVs were at 16p13.11 (nine duplications), 4q22.3 (two duplications and one deletion), 1p36.33 (one duplication and one deletion), 2p16.2 (two duplications) and 19q13.2 (two duplications). Regulation of the actin cytoskeleton was the most significantly enriched pathway in all three datasets. Other biologically plausible candidate genes and pathways included cell adhesion (TSP1, BGN, TNC), angiogenesis (JAG1, AGGF1, COL18A1) and regulation of smooth muscle gene expression (ABRA, HAND1, SMYD1, FOG2).
Conclusions: We identified multiple loci affected by rare CNVs, demonstrating the genetic heterogeneity of STAAD and implicating alterations of candidate genes at these loci in the pathogenesis STAAD. Our data predicts that rare CNVs contribute to at least 10% of sporadic, non-syndromic TAAD.
- © 2010 by American Heart Association, Inc.