CVD Risk Assessment Using Traditional Factors and Polygenic Risk Scores
- This large multi-ancestry prognostic cohort study examined the associations between polygenic risk scores (PRSs) for atherosclerotic cardiovascular disease (ASCVD) derived from European ancestry in various population subsets of diverse genetic ancestry.
- The association of PRSs with ASCVD events was statistically significant, with slightly improved risk reclassification seen predominantly in women and younger-onset disease. The risk discrimination ability of PRSs in non-European cohorts was less pronounced.
- The effect size of traditional risk factors exceeded that of PRSs by an order of magnitude.
Are polygenic risk scores (PRSs) for atherosclerotic cardiovascular disease (ASCVD) derived from European ancestry associated with ASCVD events in diverse population subsets, and can PRSs enhance the risk stratification of ASCVD outcomes?
This study leveraged data from the Million Veteran Program (MVP), a large prognostic cohort study, where participants' PRSs were derived from genome-wide association studies for coronary artery disease (CAD) and ischemic stroke. The focus was on three diverse populations (European, Black, Hispanic), and the analysis was adjusted for traditional risk factors for ASCVD. The study examined PRSs' association with incident ASCVD events such as myocardial infarction, ischemic stroke, ASCVD-related death, and composite ASCVD events. The study also assessed the predictive capacity of PRS by net reclassification improvement and C statistics. A combined genetic and traditional risk (G × E) model was constructed to evaluate whether polygenic scores improved ASCVD risk prediction over and above traditional risk factors.
The cohort included 79,151 veterans without baseline ASCVD, predominantly male (86.5%) and White (68.0%). The participants were followed for an average of 4.3 years. During this period, 6.9% of the participants experienced the first ASCVD event. The risk of ASCVD events increased with both the traditional and PRSs. The magnitude of risk was greater for the traditional risk score than the PRS. The hazard ratios (HRs) varied by race, with a 1-standard deviation increase of composite PRS increasing the hazard for ASCVD events by 11% in Black veterans, 12% in Hispanic veterans, and 20% in White veterans. Adding PRS to the traditional ASCVD risk model significantly improved reclassification of women around the intermediate risk threshold by 6.8% across all groups combined, with the most reclassification occurring among Hispanic women (19.0%), followed by Black women (10.6%), and lowest among White women (3.4%). There was a higher net reclassification improvement among younger participants. The addition of PRS to the traditional model increased the C index for all ASCVD outcomes by roughly 0.01 among Hispanic and White participants, but the incremental effects were smaller for ischemic stroke and all nondeath outcomes among Black participants.
European ancestry-derived PRSs were significantly associated with incident ASCVD, especially in women and younger-onset diseases, across multiple ancestries, including Black and Hispanic populations. Addition of PRS to traditional risk factors only modestly improved risk discrimination.
The study's large multi-ancestry cohort, including a significant representation from Black and Hispanic populations, broadens the potential utility of PRSs beyond the traditionally studied European-ancestry populations. This is a critical step in ensuring that the benefits of genomic medicine can be realized across diverse populations, although the study does acknowledge that PRS performance is reduced in these populations.
Of particular interest is the finding that PRSs were more significantly associated with ASCVD events in women and younger-onset disease, hinting at the possibility that genetic risk factors may play a larger role in these subgroups. Though modest, the observed improvements in risk reclassification could still have a substantial impact when applied to large populations at risk. Furthermore, the study challenges the traditional approach to ASCVD risk stratification by demonstrating that separate PRSs for CAD and ischemic stroke were associated with different ASCVD outcomes. A more nuanced, phenotype-specific approach in genetic risk assessment could potentially lead to more targeted prevention strategies.
Many questions remain, including delineating the role of socially defined race and ethnicity versus genetically defined ancestry in risk prediction, the best approach to combine PRSs for multiple phenotypes, and implementation at the public health and clinical practice level. This study is clearly a small step in the long and far from straightforward journey from genetic research to clinical application.
Keywords: Atherosclerosis, Coronary Artery Disease, Ethnic Groups, European Continental Ancestry Group, Genome-Wide Association Study, Genomics, Ischemic Stroke, Myocardial Infarction, Phenotype, Primary Prevention, Risk Factors, Stroke, Veterans
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