Polygenic risk and incident coronary heart disease in a large multiethnic cohort

Carlos Iribarren; Meng Lu; Roberto Elosua; Martha Gulati; Nathan D Wong; Roger S Blumenthal; Steven Nissen; Jamal S Rana

doi:10.1016/j.ajpc.2024.100661

Polygenic risk and incident coronary heart disease in a large multiethnic cohort

Am J Prev Cardiol. 2024 Mar 28:18:100661. doi: 10.1016/j.ajpc.2024.100661. eCollection 2024 Jun.

Authors

Carlos Iribarren¹, Meng Lu¹, Roberto Elosua^{2

3}, Martha Gulati⁴, Nathan D Wong⁵, Roger S Blumenthal⁶, Steven Nissen⁷, Jamal S Rana^{1

8}

Affiliations

¹ Kaiser Permanente Northern California Division of Research, Oakland, CA, USA.
² Cardiovascular Epidemiology and Genetics, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Spain and CIBER Cardiovascular Diseases (CIBERCV), Barcelona, Spain.
³ Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
⁴ Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁵ Heart Disease Prevention Program, Division of Cardiology, Department of Medicine, University of California Irvine, Irvine, CA, USA.
⁶ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁷ Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA.
⁸ Department of Cardiology, The Permanente Medical Group, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.

Abstract

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.

Keywords: Clinical utility; Coronary heart disease; Polygenic risk score; Primary prevention.