Key result
Adding polygenic information to the FH-Risk-Score fails to improve ASCVD risk prediction.
Why the study?
A high polygenic score for coronary artery disease (PRSCAD) is a strong independent predictor of ASCVD in FH patients, but its added value to the FH-Risk-Score for risk prediction is unclear.
Does the addition of a polygenic score for coronary artery disease (PRSCAD) to the FH-Risk-Score improve ASCVD risk prediction in patients with familial hypercholesterolemia?
Cohort (n=1,438)
Yes
Does the addition of a polygenic score for coronary artery disease (PRSCAD) to the FH-Risk-Score improve ASCVD risk prediction in patients with familial hypercholesterolemia?
Hazard Ratio: 1.77 (95% CI 1.2–2.61)
Absolute Event Rate: 15% vs 9%
p-value: p=0.004
The addition of a polygenic risk score to standard clinical risk scores does not significantly improve overall ASCVD risk prediction in patients with familial hypercholesterolemia.
AIM: A high polygenic score for coronary artery disease (PRSCAD) has been demonstrated to be a strong and independent predictor of atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). The objective was to investigate if the addition of a PRSCAD to the FH-Risk-Score enhances ASCVD risk prediction compared to the clinical score alone. METHODS: Data from 3 independent cohorts of patients with FH have been analysed in this longitudinal study (n=1438). The FH-Risk-Score equation was used to calculate the baseline 10-year ASCVD risk. A high PRSCAD was defined as a score > 75th percentile. The performance of the Combined score was assessed using measures of discrimination (C statistics), calibration (predicted risk vs. observed risk), and reclassification (using a 10-year risk cutoff of 20%). RESULTS: Overall, the event rate was nearly doubled in individuals having a high PRSCAD (15% vs. 9%, HR 1.77, 95% CI 1.20-2.61, P=0.004). This association was stronger in those with a genetic confirmation of FH (17% vs. 8%, HR 2.34, 95% CI 1.50-3.67, P=0.0002). The Combined score was associated with a marginally non-significant higher C-index than the FH-Risk-Score alone (0.746 to 0.750, P=0.60). The difference in C-index was significant in patients with a genetic confirmation of FH in the moderate FH-Risk-Score group (0.617 to 0.717, P=0.05). CONCLUSION: Overall, the addition of polygenic information using PRSCAD percentiles to the FH-Risk-Score estimate did not significantly enhance ASCVD risk prediction in patients with FH. Replication efforts with larger number of individuals and incident cases are warranted.
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Paquette et al. (2026) conducted a cohort in familial hypercholesterolemia (n=1,438). High polygenic score for coronary artery disease (PRSCAD > 75th percentile) vs. PRSCAD ≤ 75th percentile was evaluated on Atherosclerotic cardiovascular disease (ASCVD) (HR 1.77, 95% CI 1.20-2.61, p=0.004). Although a high PRSCAD was associated with increased ASCVD events (15% vs. 9%, HR 1.77), adding it to the FH-Risk-Score did not significantly enhance risk prediction (C-index 0.746 to 0.750, P=0.60).
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