• Joshua Elliott, Barbara Bodinier, Tom A Bond, Marc Chadeau-Hyam, Evangelos Evangelou, MoonsKarel G MKGMJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Abbas Dehghan, David C Muller, Paul Elliott, and Ioanna Tzoulaki.
• Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
• JAMA. 2020 Feb 18; 323 (7): 636645636-645.

ImportanceThe incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain.ObjectiveTo examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations.Design, Setting, And ParticipantsObservational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency-matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD.ExposuresPolygenic risk score for CAD, pooled cohort equations, and both combined.Main Outcomes And MeasuresCAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed.ResultsIn the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and -0.4% (95% CI, -0.5% to -0.4%) for noncases (overall net reclassification improvement, 4.0% [95% CI, 3.1% to 4.9%]).Conclusions And RelevanceThe addition of a polygenic risk score for CAD to pooled cohort equations was associated with a statistically significant, yet modest, improvement in the predictive accuracy for incident CAD and improved risk stratification for only a small proportion of individuals. The use of genetic information over the pooled cohort equations model warrants further investigation before clinical implementation.

18 keywords...

hide…