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Published on: June 21, 2018
Polygenic risk and incident coronary heart disease in a large multiethnic cohort
Carlos Iribarren1, Meng Lu1, Roberto Elosua2,3
1Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.
Insights
Polygenic risk scores (PRS) enhance coronary heart disease (CHD) prediction beyond traditional factors. Incorporating PRS identifies more individuals for intensive risk management, improving primary prevention strategies.
Area of Science:
- Cardiovascular Disease Epidemiology
- Genetics and Genomics
- Preventive Cardiology
Background:
- Polygenic risk scores (PRS) show promise in improving coronary heart disease (CHD) risk prediction beyond conventional risk factors.
- Despite supporting evidence, PRS are not yet integrated into clinical guidelines as a risk-enhancing factor.
- Commercial PRS, like CARDIO inCode-Score®, require validation in diverse, contemporary populations.
Purpose of the Study:
- To evaluate the predictive performance of a commercial PRS (CARDIO inCode-Score®) for incident CHD.
- To compare the PRS performance against the established Pooled Cohorts Equations (PCE) in a multi-ethnic cohort.
- To assess the impact of PRS on risk reclassification and identification of individuals for intensified preventive measures.
Main Methods:
- A contemporary, multi-ethnic cohort of 63,070 participants without prior CHD was followed for incident events over 14 years.
- Cox regression models were used to assess the association between PRS and CHD, adjusting for genetic ancestry and risk factors.
- Risk discrimination (C-statistic) and net reclassification improvement (NRI) were calculated to quantify the PRS's added value over PCE.
Main Results:
- An increased PRS was significantly associated with higher incident CHD risk (aHR per SD: 1.18; upper vs. lower quintile: 1.66).
- The PRS demonstrated consistent associations across sexes and ethnic groups, with strongest effects early in follow-up.
- Inclusion of PRS improved risk prediction, with a notable NRI of 9.7% in intermediate PCE risk individuals, identifying 10% more candidates for statin therapy.
Conclusions:
- The commercial CARDIO inCode-Score® PRS effectively improves CHD risk prediction in a multi-ethnic population.
- Integrating PRS can enhance the identification of individuals who would benefit from more intensive risk factor modification and primary prevention strategies.
- These findings support the potential utility of PRS in clinical decision-making for CHD prevention.
Objective:
Many studies support the notion that polygenic risk scores (PRS) improve risk prediction for coronary heart disease (CHD) beyond conventional risk factors. However, PRS are not yet considered risk-enhancing factor in guidelines. Our objective was to determine the predictive performance of a commercially available PRS (CARDIO inCode-Score®) compared with the Pooled Cohorts Equations (PCE) in a contemporary, multi-ethnic cohort.
Methods:
Participants (n = 63,070; 67 % female; 18 % non-European) without prior CHD were followed from 2007 through 12/31/2022. The association between the PRS and incident CHD was assessed using Cox regression adjusting for genetic ancestry and risk factors. Event rates were estimated by categories of PCE and by low/intermediate/high genetic risk within PCE categories; risk discrimination and net reclassification improvement (NRI) were also assessed.
Results:
There were 3,289 incident CHD events during 14 years of follow-up. Adjusted hazard ratio (aHR) for incident CHD per 1 SD increase in PRS was 1.18 (95 % CI:1.14-1.22), and the aHR for the upper vs lower quintile of the PRS was 1.66 (95 % CI:1.49-1.86). The association was consistent in both sexes, in European participants compared with all minority groups combined and was strongest in the first 5 years of follow-up. The increase in the C-statistic was 0.004 (0.747 vs. 0.751; p < 0.0001); the NRI was 2.4 (0.9-3.8) for the entire cohort and 9.7 (7.5-12.0) for intermediate PCE risk individuals. After incorporating high genetic risk, a further 10 percent of participants at borderline/intermediate PCE risk would be candidates for statin therapy.
Conclusion:
Inclusion of polygenic risk improved identification of primary prevention individuals who may benefit from more intensive risk factor modification.
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