Polygenic risk in early-onset coronary artery disease with low prevalence of traditional cardiovascular risk factors

Aims: We aimed to investigate the potential role of polygenic risk in early-onset coronary artery disease (CAD) and recurrence of major adverse coronary events (MACE) in patients with low prevalence of traditional cardiovascular risk factors (CVRFs). Methods: This was a prospective study enrolling a cohort of patients with early-onset CAD (<50 years) despite no/few traditional CVRFs. Baseline CAD risk was calculated according to Systematic Coronary Risk Evaluation 2 (SCORE2). The CAD-polygenic risk score (PGS) developed by Khera et al. was computed for the patients and compared with a local control population of unselected individuals. MACE were collected at long term follow-up. Results: We enrolled 42 patients [81% males; median age 44 years, interquartile range (IQR) 40-46] presenting with early-onset CAD from 2014 to 2021. The majority of them (72%) had ≤1 modifiable CVRF with a 3.9% mean risk of developing CV event at 10 years. The control population consisted of 1408 individuals (51% males; median age 39 years, IQR 29-49). We found a significant positive shift in CAD-PGS distribution among early-CAD patients compared with controls (P value < 0.0001). Over a median follow-up of 104 months, 40.5% of patients experienced a new MACE, with an annual incidence rate of 8 (IQR 5-13) per 100 persons/year. Conclusions: In patients with early-onset CAD despite low clinical risk score, we found CAD-PGS values significantly higher than in the general population and a high rate of recurrence of MACE. These findings highlight the potential of PGS in refining CAD risk stratification, properly tailoring prevention strategies.