Rare Copy Number Variants Disrupt Genes Regulating Vascular Smooth Muscle Cell Adhesion and Contractility in Sporadic Thoracic Aortic Aneurysms and Dissections

Abstract

Conclusion: Rare copy number variants that disrupt smooth muscle cell (SMC) adhesion or contraction contribute to familial and sporadic thoracic aortic aneurysm (TAA) disease. Summary: A family history of similar disease is present in 20% of patients with TAAs or dissections. The phenotype is inherited as an autosomal-dominant, with variable expression and incomplete penetrance (Milewicz DM et al [Am J Cardiol 1998;82:474-9]). Genes have been identified that contribute to familial TAA and dissection. They encode SMC-specific isoforms of actin and myosin, regulate expression of contractile proteins by vascular SMCs, or involve mutations of SMC adhesive or cytoskeletal proteins (Grainger DJ et al [J Cell Sci 1998;111:2977-88]; Sheen VL [Neurology 2005;64:254-62]). The authors hypothesized that variations in modifying genes influence an individual's susceptibility to TAA or dissection. Variations in copy numbers of genes, so-called copy number variation (CNV), can increase the risk for certain diseases. The authors hypothesized CNVs result in structural variance of the aortic wall that contributes to risk for TAAA and dissection, and given the pathogenesis of TAA, it is also likely these genes involve vascular SMC contractility. This was a genome-wide analysis of genes that potentially contribute to TAA or dissection in 548 cases of sporadic TAA or dissection. Compared with controls, 47 CNV regions were identified that were enriched or unique to patients with TAA or dissection. The CNVs effected genes that regulated SMC adhesion or contractility or that interacted with SMC isoforms of α-actin and β-myosin. Both cause familial TAA or dissection when altered. There was also replication of rare CNVs in an independent cohort of sporadic TAAs or dissections (n = 387) and in a cohort of inherited TAAs (n = 88). The prevalence of CNVs was higher in patients with familial TAAs or dissection than in those with sporadic TAAs or dissection (P = .03). Comment: Genetic and environmental factors are both important in aneurysm disease. Gene products that relay environmental signals affecting genes that regulate SMC function would seem to be ideal candidates to modify the pathogenesis of aneurysm disease. The authors' findings are consistent with a genetic model where CNV mutations contribute to aneurysm causation or predisposition. If such variants could be tested for clinically, patients with appropriate environmental factors placing them at risk for aneurysm disease could have their potential risk of aneurysm development identified with genetic testing.