A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment

Abstract

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge.Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk.The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutationnegative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.

Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia

“…The Cardio inCode® score (CiC score) (22), a PRS for CAD, was included only in the Lipid inCode® test and is a measure of a patient's genetic risk for coronary disease independent of other cardiovascular risk factors (including hypercholesterolaemia) and of family history of CHD (22,42,43). There is evidence that a high CAD PRS can significantly modify the disease phenotype (higher prevalence of CVD events and higher number of events) after adjusting for established predictors of CAD risk, even in the context of a severe monogenic disease such as FH (44)(45). A high CAD PRS has also been shown to be associated with greater subclinical atherosclerosis in FH patients, as assessed by coronary artery calcium score, even after adjusting for the presence of pathogenic FH variants (45).…”

“…There is evidence that a high CAD PRS can significantly modify the disease phenotype (higher prevalence of CVD events and higher number of events) after adjusting for established predictors of CAD risk, even in the context of a severe monogenic disease such as FH (44)(45). A high CAD PRS has also been shown to be associated with greater subclinical atherosclerosis in FH patients, as assessed by coronary artery calcium score, even after adjusting for the presence of pathogenic FH variants (45). Although the utility of this additional genetic data in clinical practice should be confirmed with large scale clinical trial data, and is beyond the scope of this study, it may refine CVD risk prediction in FH patients and this could lead to a more personalized approach to patient management and therapy.…”

Applying implementation science to improve care for familial hypercholesterolemia

“…Once prompted, clinicians should be familiar with the different risk scores used to predict cardiovascular disease including a genetic risk score [38] and risk models [39,40]. A genetic risk score was found to be associated with increased odds of cardiovascular disease (variant positive odd ratio [OR] ¼ 3.3; 95% CI 1.3-8.2 and variant negative OR ¼ 1.8; 95% CI 1.0-3.3) [38]. A clinical risk model was found to have fair fit in primary (C-statistic: 0.71; 95% CI: 0.68-0.75) and secondary prevention (0.65; 95% CI 0.60-0.70) patients [39].…”

Genetic Risk Score for Coronary Heart Disease: Review

“…Patients with FH who are at high GRS risk may benefit from a more active intervention, including lifestyle changes and aggressive lipid-lowering therapy. Further evaluation of the usefulness of GRSs, including their role in the management of patients with FH in the clinic, requires a study on prospective cohorts [87].…”