Familial SCAD linked to aggregation of common genetic variants
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Key takeaways:
- Polygenic risk was associated with odds of familial SCAD and likelihood of sporadic cases.
- Previously implicated genes tied to connective tissue disorders were associated with familial SCAD.
Researchers reported that high concentrations of common genetic variants within families were associated with increased inherited risk for spontaneous coronary artery dissection.
Rarer genes associated with inherited connective tissue disorders were not associated with spontaneous coronary artery dissection (SCAD) risk, according to data published in JAMA Cardiology.
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“In the last 5 years, our understanding of SCAD genetics has developed rapidly. Beginning in 2019, common variants were identified, and the first polygenic risk score (PRS) for SCAD was reported. ... Recent data highlight the role of common genetic variation in numerous familial adult-onset diseases,” Ingrid Tarr, BSc, of the Victor Chang Cardiac Research Institute in Darlinghurst, Australia, and colleagues wrote. “Given the established genetic contribution to SCAD but the lack of understanding of familial disease, we investigated the role of common SCAD polygenic risk in the largest familial SCAD cohort assembled to date, to our knowledge.”
For this study, Tarr and colleagues assessed whether common genetic variants are associated with familial SCAD — defined as at least two affected individuals of no more than third-degree relatedness — and whether rare variants were the exception or the norm.
Their cohort consisted of 1,352 genotyped individuals, of whom 1,127 were older healthy controls of European ancestry (60% women), 173 had sporadic SCAD, and there were 13 families with SCAD, including 27 affected individuals and 18 SCAD-free relatives. The remaining seven individuals included two unrelated individuals with sporadic SCAD and five first-degree relatives.
The researchers calculated PRS for SCAD for all participants and searched for rare variants in genes associated with connective tissue disorders.
The PRS consisted of seven single nucleotide variants.
Polygenic risk score to predict SCAD
Among 188 individuals with SCAD, 94% were women, including 25 of 27 with familial SCAD and 163 of 173 with sporadic SCAD, according to the study.
Among 12 unaffected individuals from families with SCAD, 50% were women.
Compared with healthy controls, every 1 standard deviation increase in PRS was associated with more than twofold likelihood being an affected family member or having sporadic SCAD (OR for affected family member = 2.14; 95% CI, 1.78-2.5; P = .000196; OR for sporadic SCAD = 1.63; 95% CI, 1.37-1.89; P = .000569).
PRS was not associated with odds of being an affected family member or having sporadic SCAD among unaffected family members compared with healthy controls (P = .91).
Moreover, individuals with familial SCAD (OR = 3.7; 95% CI, 2.93-4.47; P = .001) and those with sporadic SCAD (OR = 2.51; 95% CI, 1.98-3.04; P = .001) were overrepresented in the top quintile of the control PRS distribution, according to the study.
The researchers reported that affected individuals within a family did not share rare deleterious variants in connective tissue disorder-associated genes.
“Here, we showed that the SCAD PRS was strongly associated with familial SCAD risk,” the researchers wrote. “This was evidenced by a clear association of disease risk with the SCAD PRS in affected family members with SCAD, a high proportion of affected family members with a high SCAD PRS, and a higher SCAD PRS in affected vs unaffected first-degree relatives. However, no rare, likely pathogenic, or pathogenic variants were found to segregate with disease in any family across connective tissue disorder-associated genes. These findings provide novel insight into the genetic underpinnings of familial forms of SCAD.”
‘First step’ toward SCAD prevention
In a related editorial, Pradeep Natarajan, MD, MMSc, director of preventive cardiology and the Fireman Endowed Chair in Vascular Medicine at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, and Sharlene M. Day, MD, director of translational research in the division of cardiovascular medicine and Cardiovascular Institute and Presidential Associate Professor at Penn Medicine, discuss the utility of PRS for the prevention of SCAD.
“Clinical risk factors for SCAD include younger age, female sex, pregnancy, and fibromuscular dysplasia. However, these factors remain insufficient for predicting risk for developing SCAD,” Natarajan and Day wrote. “Recent genome-wide association studies of SCAD have further implicated common genetic variation in SCAD. In addition to using these data to prioritize mechanistic hypotheses, these alleles in aggregate may be used in a PRS to predict risk for SCAD.
“Although the genetic discovery in SCAD is still in its nascency, these observations shift the emphasis from single gene discovery to polygenic contributions to explain familial clustering without classic mendelian inheritance,” they wrote. “Identifying family members at risk of experiencing SCAD is the first step toward implementation of preventive approaches.”
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