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Polygenic risk score predicts prevalence of cardiovascular disease in patients with familial hypercholesterolemia
Martine Paquette1, Michael Chong2, Sébastien Thériault3
1Nutrition, Metabolism and Atherosclerosis Clinic, Institut de recherches cliniques de Montréal, Québec, Canada.
Insights
Genetic risk scores in familial hypercholesterolemia (FH) modify cardiovascular disease (CVD) risk. Polygenic scores, particularly for coronary artery disease (CAD), can help predict CVD events in FH patients.
Area of Science:
- Genetics
- Cardiology
- Metabolic Diseases
Background:
- Familial hypercholesterolemia (FH) is a severe monogenic disorder.
- Clinical risk factors and common genetic variants can influence cardiovascular disease (CVD) risk in FH.
Purpose of the Study:
- To assess the polygenic contribution to lipid traits and CVD risk in FH patients.
- To evaluate the utility of genetic risk scores (GRSs) for predicting these outcomes.
Main Methods:
- Retrospective cohort study of 725 FH patients with identified mutations.
- Association analysis of GRSs for coronary artery disease (GRSCAD), LDL cholesterol (GRSLDL-C), HDL cholesterol (GRSHDL-C), and triglycerides (GRSTG).
Main Results:
- 32% of FH subjects experienced a CVD event before their first visit.
- Higher GRSLDL-C correlated with increased LDL-C levels.
- GRSCAD was strongly associated with CVD events, even after adjusting for risk factors, with higher GRSCAD tertiles showing significantly increased event prevalence and number.
Conclusions:
- Common genetic variants significantly modify the disease phenotype in FH.
- GRSCAD can enhance CVD risk prediction in FH patients.
- GRSCAD may facilitate a more personalized therapeutic strategy for FH.
Background:
Although familial hypercholesterolemia (FH) is a severe monogenic disease, it has been shown that clinical risk factors and common genetic variants can modify cardiovascular disease (CVD) risk.
Objective:
The aim of the study was to evaluate the polygenic contribution to lipid traits and CVD in FH using genetic risk scores (GRSs).
Methods:
Among the 20,434 subjects attending the lipid clinic, we identified and included 725 individuals who carried an FH causing mutation in this retrospective cohort study. We evaluated the association of GRSs for several traits including coronary artery disease (CAD; GRSCAD) as well as plasma concentrations of low-density lipoprotein cholesterol (LDL-C; GRSLDL-C), high-density lipoprotein cholesterol (GRSHDL-C) and triglycerides (GRSTG).
Results:
A total of 32% (n = 231) of FH subjects presented a CVD event before their first visit. Patients in the highest GRSLDL-C tertile presented an LDL-C 0.4 mmol/L (15.5 mg/dL) higher than the subjects in the lowest tertile (P = .01). The GRSCAD was strongly associated with CVD events (odds ratio 1.80; 95% confidence interval 1.14-2.85; P = .01) even after adjustment for cardiovascular risk factors. Compared with subjects in the first tertile, those in the third GRSCAD tertile had a significantly higher prevalence of events (40.9% vs 24.7%, P < .0001) and a significantly higher number of events (average 0.97 vs 0.57 [P = .0001] events per individual).
Conclusion:
These results indicate that even in the context of a severe monogenic disease such as FH, common genetic variants can significantly modify the disease phenotype. The use of the 192-SNPs GRSCAD may refine CVD risk prediction in FH patients and this could lead to a more personalized approach to therapy.
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