Rare genetic variants may be enriched in patients with high-risk spontaneous coronary artery dissection

1. This prospective case-control study showed that approximately 20% of patients with spontaneous coronary artery dissection with high-risk characteristics had a rare genetic variant associated with vascular connective tissue disease.

2. Variants in the COL3A1 gene, a gene associated with connective tissue disease, was the most common variant observed in patients with spontaneous coronary artery dissection.

Evidence Rating Level: 3 (average)

Course of study: Spontaneous coronary artery dissection (SCAD) is a cause of myocardial infarction, most often in younger women, not due to atherosclerosis. A growing body of evidence suggests that there is a genetic basis for SCAD with genes known to cause connective vascular diseases (CTDs); However, the extent and effect of these genes have not yet been fully elucidated. This case-control study performed whole exome (WES) sequencing to assess whether individuals with high-risk SCAD traits are associated with an increased likelihood of carrying rare genetic variants. Patients with non-atherosclerotic SCAD between May 15, 2014 and August 14, 2018 were recruited from the Canadian SCAD registry. WES was performed by comparing those with SCAD to matched controls or the Genome Aggregation Database (gnomAD). The primary endpoint was the burden of genetic variants in patients with high-risk SCAD. Among the vascular CTD genes, there were 23 variants in 13 of the 22 identified CTD genes. The identified genetic variants of all CTD genes were significantly greater in the high-risk SCAD cohort (n = 94) than in the gnomAD cohort (n = 125,748) (odds ratio [OR]: 2.6 [95% CI: 1.6-4.2]). Variants of these identified genes were observed in 16 of 94 (17%) SCAD patients. Among the identified CTD genes are variants in the COL3A1 gene were most prevalent; this gene carried an OR of 13.4 (95% CI: 4.9-36.2) to be identified in the high-risk SCAD cohort compared to healthy controls. In addition, variants were identified in the genome-wide association study (GWAS) in 6 of 94 (6.4%) individuals with high-risk SCAD (OR: 2.6 [95% CI: 1.6-8.2) where the LRP1 gene was most enriched (OR: 3.7 [95% CI: 1.4-10.1]). Overall, this WES case control study observed rare gene variants in approximately 20% of patients with SCAD, highlighting the genetic basis for SCAD and its association with vascular CTDs. This study was limited by its small sample size, which limited its statistical power.

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Click here to read the study in JAMA Cardiology

Click here to read an accompanying editorial in JAMA Cardiology

Relevant reading: Prospective cardiovascular genetic evaluation in spontaneous coronary artery dissection

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