Martine Paquette1, Michael Chong2, Sébastien Thériault3, Robert Dufour4, Guillaume Paré5, Alexis Baass6. 1. Nutrition, Metabolism and Atherosclerosis Clinic, Institut de recherches cliniques de Montréal, Québec, Canada. 2. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton General Hospital, Ontario, Canada. 3. Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, Canada. 4. Nutrition, Metabolism and Atherosclerosis Clinic, Institut de recherches cliniques de Montréal, Québec, Canada; Department of Nutrition, Université de Montréal, Québec, Canada. 5. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton General Hospital, Ontario, Canada; Population Genomics Program, Department of Clinical Epidemiology and Biostatistics, McMaster University, Ontario, Canada; The Department of Pathology and Molecular Medicine, McMaster University, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, Ontario, Canada. 6. Nutrition, Metabolism and Atherosclerosis Clinic, Institut de recherches cliniques de Montréal, Québec, Canada; Division of Experimental Medicine, Department of Medicine, McGill University, Québec, Canada; Division of Medical Biochemistry, Department of Medicine, McGill University, Québec, Canada. Electronic address: alexis.baass@ircm.qc.ca.
Abstract
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.
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 FHpatients and this could lead to a more personalized approach to therapy.
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