Dissecting the Genomics of Spontaneous Coronary Artery Dissection

摘要

The integration of genetic sequencing into clinical cardiology has significantly impacted the management of individuals and families with inherited cardiovascular disorders. Although a genetics-guided approach into the diagnosis and management of cardiomyopathies and arrhythmogenic disorders has been rapidly expanding, the use of gene sequencing to understand rare pathogenic or likely pathogenic (P/LP) variants to cause vascular disorders has been largely limited to familial thoracic aortic aneurysm and dissection, including Loeys-Dietz and Marfan syndrome.1 Outside of rare variant analysis, there has been a massive effort over the past 2 decades to understand how common genetic variation modifies complex disease risk, most notably within coronary artery disease (CAD) where there are now >200 gene loci associated with CAD,2-6 with the majority of genome-wide association studies (GWAS) CAD genes believed to influence disease risk by regulating progression of disease within the vessel wall itself. define a patient population which differs from those with typical CAD risk factors.7,8 Patients with SCAD are more often women, are typically younger, and often have minimal modifiable risk factors.9 Although patients with fibromuscular dysplasia have been identified as having a higher risk for SCAD, in the past 5 years, GWAS of SCAD have further suggested that complex genetics influences SCAD risk, highlighting a genetic basis of disease. In a series of GWAS studies in SCAD, 5 regions of the genome had been identified to meet genome-wide significance including 1q21.2 (C1orf51'),'0,u 6p24.1 (PHACTR1/EDN1),10-12 12q13.3 (LRP1),10,11 15q21.1 (FBN1),11 and 21q22.11 (LINC00310).10,11 This list of 5 loci has just recently been expanded in a new preprint, where Adlam et al13 have revealed a meta-analysis of SCAD GWAS revealing 12 new loci, making a total of 17 loci to meet genome-wide significance for SCAD. Indeed, further population level genetic analysis with a polygenic risk score has confirmed that there are opposing genetic mechanisms between SCAD-related MI and atherosclerotic MI.10,13 However, the complex disease genetics of SCAD appears limited and increasing reports of SCAD associated with heritable connective tissue disorders (CTDs)14 and multigenerational family pedigrees with SCAD15 further suggests an underappreciated rare disease genetics component to this condition.