Identification of a Risk Locus Suggests SCAD May be Genetically Determined Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection

In the largest study conducted to date for Spontaneous coronary artery dissection (SCAD), the first genetic risk factor was identified. The findings, published in JACC, suggested that this genetic link could contribute to the clinical overlap between SCAD and fibromuscular dysplasia (FMD).

Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women, accounting for 23% to 36% of AMI cases in this population, and is a rare cause of sudden cardiac death. SCAD also is the most common cause of pregnancy-associated AMI, although AMI in pregnant women accounts for only 2% to 18% of all SCAD cases. SCAD is caused by the development of an intimal tear and flap or an intramural hematoma in the outer third of the tunica media of the vessel wall, which leads to external compression of the true lumen and coronary insufficiency, myocardial ischemia, and infarction.

Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. Thus, this study sought to test the association between the rs9349379 genotype and SCAD. The investigators analyzed results from case-control studies from France, United Kingdom, United States, and Australia to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. The study demonstrated that previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.

Highlighting an important feature of the study, Dr. Nabila Bouatia-Naji of the French Institute of Health and Medical Research (Inserm) stated, “In this large genetic study conducted in >1,000 SCAD patients and 7,200 controls, robust and replicated associations are reported between rs9349379, a common noncoding variant in the PHACTR1/EDN1 locus, and the risk of SCAD. This is the first report showing that a genetic risk locus for SCAD is estimated to contribute to an increased risk of 70% among carriers of the A allele, but the study did not partition age or the specific phenotypic subgroups, namely, R-SCAD and P-SCAD subjects.”Summarizing the results of the study, primary author Dr. David Adlam, Senior Lecturer, Department of Cardiovascular Sciences, University of Leicester,  UK wrote, “This study reports that rs9349379 is the first genetic risk locus for SCAD. The previously reported association between this common variant and other vascular disorders, especially FMD, provides a genetic explanation for the established clinical associations among these disorders. Further studies will be required to confirm the relative importance of the endothelin mechanistic pathway and its relevance to SCAD and FMD risks.” Indeed, identification of a risk locus suggests that SCAD may be genetically determined with a complex pattern of inheritance. Genetic susceptibility to SCAD through the PHACTR1/EDN1 locus is shared with FMD. However, further research is necessary to establish the molecular mechanisms responsible for the clinically observed associations between SCAD and FMD.