Association of the PHACTR1/EDN1 Genetic Locus With Spontaneous Coronary Artery Dissection.
Adlam D., Olson TM., Combaret N., Kovacic JC., Iismaa SE., Al-Hussaini A., O'Byrne MM., Bouajila S., Georges A., Mishra K., Braund PS., d'Escamard V., Huang S., Margaritis M., Nelson CP., de Andrade M., Kadian-Dodov D., Welch CA., Mazurkiewicz S., Jeunemaitre X., DISCO Consortium None., Wong CMY., Giannoulatou E., Sweeting M., Muller D., Wood A., McGrath-Cadell L., Fatkin D., Dunwoodie SL., Harvey R., Holloway C., Empana J-P., Jouven X., CARDIoGRAMPlusC4D Study Group None., Olin JW., Gulati R., Tweet MS., Hayes SN., Samani NJ., Graham RM., Motreff P., Bouatia-Naji N.
BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. 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. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The 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. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.