Clinical Conditions and Their Impact on Utility of Genetic Scores for Prediction of Acute Coronary Syndrome

Abstract

Background - Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease (CHD). Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. Methods - We explored the association between 405 clinical conditions diagnosed before baseline and 9,080 incident cases of ACS in 387,832 individuals from the UK Biobank. Results were replicated in 6,430 incident cases of ACS in 177,876 individuals from FinnGen. Results - We identified 80 conventional (e.g., stable angina pectoris (SAP), type 2 diabetes mellitus) and unconventional (e.g., diaphragmatic hernia, inguinal hernia) associations with ACS. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of SAP yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction p-value=2.87×10-8) risk for ACS in individuals with SAP (HR=1.163 [95% CI: 1.082-1.251]) compared to individuals without SAP (HR=1.531 [95% CI: 1.497-1.565]). These findings were replicated in FinnGen (interaction p-value=1.38×10-6). Conclusions - In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable CHD. PS may be more appropriate for prediction of ACS in asymptomatic individuals than symptomatic individuals with clinical suspicion for CHD.

Cardiovascular Family History Increases the Risk of Disease Recurrence After a First Myocardial Infarction

“…Presumably, as all included patients in this study had a very high intrinsic risk of subsequent ASCVD events, the distribution of rASCVD risks in this population might have been narrow enough to render only small incremental effects on C‐index difference, regardless of the positive isolated HRs of risk factors. 35 Similarly to the interpretations of the leveling effect of stable angina pectoris on associations between a polygenic risk score and acute coronary syndrome as studied by Lee et al, 25 we cannot exclude that the association between a family history of ASCVD and rASCVD observed in this paper could be mitigated owing to index event bias, that is, that the selection of individuals based on a prevalent disease may influence associations between previously established risk factors and disease recurrence.…”

“… 24 Similarly, the association between a polygenic risk score and acute coronary syndrome was found to be weaker in individuals with known stable angina pectoris as compared with individuals without known angina pectoris. 25 In contrast, several GRSs have shown to be positively associated with rASCVD. 4 , 26 , 27 , 28 Importantly, the family history studied in this paper may represent a composite of both genetic and environmental familial effects on cardiovascular risk.…”

Current State and Future of Polygenic Risk Scores in Cardiometabolic Disease: A Scoping Review

“…Thirty-four studies published PRSs of CAD that met the inclusion criteria of the scoping review (Table 4). 13,15,33–64 A reasonable degree of ancestral diversity was observed in the derived PRSs, including East Asian, Hispanic, African, and Middle Eastern. However, studies with sample populations of European ancestry were by far most common.…”

“…Jung et al 28 constructed a PRS for cerebrovascular disease that better predicted stroke risk than traditional risk factors but only observed this effect for individuals <40 years of age. 28 Lee et al 49 considered the role of PRSs in primary and secondary prevention of CAD. They reported a more significant association of the PRS with acute coronary syndrome in individuals without stable angina pectoris than in those with stable angina pectoris, suggesting that a PRS is likely more appropriate in an asymptomatic population.…”

Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease

“…Clinical utility of PRSs remains limited because of the low relative risk predicted and heterogeneity of scores among individuals of the same phenotype. However, continuing studies are exploring clinical scenarios where these scores might provide added benefit to existing algorithms that rely on serum and clinical diagnostic markers 78 , 79 or where they can be used to understand the phenotypic variability for individuals with a high-risk monogenic predisposition. 80 , 81 , 82 Despite the many challenges in the field of rare disease genetics and PRSs in general, we believe that PRSs can contribute significantly to our understanding of the genetic architecture of rare, understudied disorders like CHD, and we hope that, as PRS methods continue to improve, additional insight into and knowledge of the causes of CHD can be used to improve long-term outcomes in affected individuals.…”