Key result
rs9349379-A allele linked to ~67% higher risk of spontaneous coronary artery dissection.
Why the study?
PHACTR1/EDN1 is a genetic risk locus for vascular diseases including FMD and CAD, prompting investigation into its association with SCAD.
Does the rs9349379-A allele increase the risk of spontaneous coronary artery dissection?
Meta-Analysis (n=8,245)
Yes
Does the rs9349379-A allele increase the risk of spontaneous coronary artery dissection?
Odds Ratio: 1.67 (95% CI 1.5–1.86)
p-value: p=1.10 x 10^-21
This study identifies the first genetic risk factor for SCAD, providing a molecular link that may explain the clinical overlap between SCAD and fibromuscular dysplasia.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Why is this important? Because if we understand that it is not as rare as we initially thought, people maybe will start looking for it and making the diagnosis. It's just about the perception in the clinics. If the people now understand from our study, and from other studies also, that SCAD is not that rare, it may improve how cardiovascular disease is dealt with for middle-age women who are in theory considered protected from cardiovascular disease.”
“In this study we investigated whether this factor was also associated with SCAD. And the answer is yes, this genetic factor – the A allele of the genetic variant rs9349379 located in the PHACTR1 gene (which stands for Phosphatase and actin regulator 1) – is also a risk factor for SCAD. Interestingly, it also appears to give a small protective effect from a classic heart attack, for which another allelic form of the same genetic variant (G) is already known to increase the risk in both men and women.”
“The observation that the same genetic variant can promote SCAD and protect against coronary artery disease suggests that an equilibrium is necessary for optimal coronary health, in which excessive vasoconstriction can accelerate atherosclerosis, whereas excessive vasodilation favors dissection.”
Provides first genetic anchor for SCAD; extends PHACTR1/EDN1 locus associations from FMD and CAD.
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.
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Adlam et al. (2019) conducted a meta-analysis in Spontaneous coronary artery dissection (SCAD) (n=8,245). rs9349379-A allele (PHACTR1/EDN1 locus) vs. Non-carriers / Controls was evaluated on Risk of spontaneous coronary artery dissection (OR 1.67, 95% CI 1.50 to 1.86, p=1.10 x 10^-21). The rs9349379-A allele was associated with a significantly higher risk of spontaneous coronary artery dissection (OR 1.67).
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