NEW YORK – An international team has identified genetic risk variants and genes associated with spontaneous coronary artery dissection (SCAD), a form of heart disease that is overrepresented in women under 60 years old.
"Our study reports on a considerable number of new genetic variations that we find to be associated with an increased risk for spontaneous coronary artery dissection (SCAD), a neglected form of myocardial infarction," senior and co-corresponding author Nabila Bouatia-Naji, with INSERM Université Paris Cité's Paris Cardiovascular Research Center, said in an email.
She noted that the results, published in Nature Genetics on Monday, suggested the condition "is genetically different from the most common form of myocardial infarction."
Using a genome-wide association study meta-analysis involving 1,917 individuals with SCAD and nearly 9,300 unaffected control individuals, all of European ancestry, the researchers narrowed in on 16 SCAD-associated loci, including 11 associations not reported in the past. Along with an overrepresentation of SCAD-linked loci at enhancer regions, the variant associations involved expression quantitative trait loci with known activity in blood, fibroblasts, or coronary-related tissue types.
"Importantly," the authors reported, "we show that several common genetic risk loci for SCAD are shared with [coronary artery disease] but have a directionally opposite effect and a different genetic contribution of established cardiovascular risk factors."
"This research confirms that there are multiple genes involved in determining the risk of a person having a SCAD," co-first and co-corresponding author David Adlam, a cardiology researcher affiliated with Glenfield Hospital and the University of Leicester, said in a statement. "These genes give us the first key insight into the underlying causes of this disease and provide new lines of enquiry, which we hope will guide future new treatment approaches."
Using functional clues from efforts such as ENCODE, together with insights from past transcriptome-wide association studies, for example, the team focused in on vascular smooth muscle cells and artery fibroblast cells, where regulatory activity by SCAD-linked loci appeared to be enhanced.
In contrast to other forms of coronary artery disease, which have been linked to processes such as lipid metabolism and inflammation, the researchers' new results revealed associations between SCAD and genes from pathways involved in extracellular matrix biology and artery structure maintenance. They also detected an apparent causal role for high blood pressure in SCAD.
"[B]lood pressure, even without clinical hypertension, is a major determinant of the risk of SCAD," Bouatia-Naji said.
These and other results may eventually help to pin down new treatment strategies that are specific to SCAD, while helping to understand the biological underpinnings of a heart condition that is mainly found in young women, Bouatia-Naji said, noting that SCAD "occurs mostly in women in their early 40s who rarely present the classical risk factors like high cholesterol or diabetes."
In particular, the investigators saw signs that a blood coagulation contributor gene called F3, a tissue factor gene, is regulated by a SCAD-associated locus on chromosome 1 region. Blood coagulation, in turn, appears to influence the formation of hematomas behind coronary artery dissection.
"While most of the risk loci were previously reported in at least another cardiovascular disease, we found that a locus on chromosome 1 is potentially specific to SCAD," Bouatia-Naji explained.
"We leverage integrative functional annotations to prioritize genes that are likely to be regulated in [vascular smooth muscle cells] and the fibroblasts of arteries," the authors wrote. "Insights from the biological functions of genes highlight the central role of extracellular matrix integrity and reveal impaired tissue coagulation as a novel potential mechanism for SCAD."