Polygenic risk scores for coronary artery disease and subsequent event risk amongst established cases

Background: There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. Methods: Using two baseline subsamples of UK Biobank: Prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. Results: A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001]. Conclusions: Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.