Polygenic Contribution in Individuals With Early-Onset Coronary Artery Disease
Sébastien Thériault1, Ricky Lali1, Michael Chong1
1From the Department of Pathology and Molecular Medicine (S.T., G.P.), Department of Biochemistry and Biomedical Sciences (R.L.), and Division of Cardiology, Department of Medicine (J.L.V., M.K.N.), Hamilton Health Sciences, McMaster University, Ontario; Population Health Research Institute, Hamilton, Ontario (S.T., M.C., G.P.); and Quebec Heart and Lung Institute Research Center, Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Canada (S.T.).
Insights
A high number of common genetic variants contribute to early-onset coronary artery disease (EOCAD), a polygenic risk similar to familial hypercholesterolemia. This genetic risk score could aid in diagnosing EOCAD, even without rare mutations.
Area of Science:
- Cardiovascular Genetics
- Polygenic Risk Scores
- Coronary Artery Disease Etiology
Background:
- Monogenic disorders explain only a small fraction of early-onset coronary artery disease (EOCAD) cases.
- A hypothesis suggests common genetic variants may collectively increase EOCAD risk.
- This polygenic effect could mimic Mendelian forms of coronary artery disease, like familial hypercholesterolemia.
Purpose of the Study:
- To investigate the polygenic contribution to EOCAD.
- To assess the prevalence of a significant polygenic risk in EOCAD patients.
Main Methods:
- Calculated a genetic risk score (GRS182) using 182 common variants in 111,418 UK Biobank participants.
- Compared GRS182 in individuals with EOCAD (n=96) versus controls.
- Validated findings in a local EOCAD cohort (n=30).
Main Results:
- Individuals with EOCAD had significantly higher GRS182 (P=3.21×10⁻⁹).
- Each 1 SD increase in GRS182 corresponded to an 1.84-fold increased EOCAD risk.
- An estimated 1 in 53 individuals with EOCAD had a polygenic risk similar to familial hypercholesterolemia.
Conclusions:
- A significant polygenic contribution is evident in EOCAD, potentially more common than familial hypercholesterolemia.
- Polygenic risk assessment may be valuable in the diagnostic workup for EOCAD.
- This approach can identify high-risk individuals even in the absence of monogenic mutations.
Background:
Despite evidence of high heritability, monogenic disorders are identified in a minor fraction of individuals with early-onset coronary artery disease (EOCAD). We hypothesized that some individuals with EOCAD carry a high number of common genetic risk variants, with a combined effect similar to Mendelian forms of coronary artery disease, such as familial hypercholesterolemia.
Methods And Results:
To confirm the polygenic contribution to EOCAD (age of ≤40 years for men and ≤45 years for women), we calculated in 111 418 British participants from the UK Biobank cohort a genetic risk score (GRS) based on the presence of 182 independent variants associated with coronary artery disease (GRS182). Participants with a diagnosis of EOCAD who underwent a revascularization procedure (n=96) had a significantly higher GRS182 (P=3.21×10-9) than those without EOCAD. An increase of 1 SD in GRS182 corresponded to an odds ratio of 1.84 (1.52-2.24) for EOCAD. The prevalence of a polygenic contribution that increased EOCAD risk similar to what is observed in heterozygous familial hypercholesterolemia was estimated at 1 in 53. In a local cohort of individuals with EOCAD (n=30), GRS182 was significantly increased compared with UK Biobank controls (P=0.001). Seven participants (23%) had a GRS182 corresponding to an estimated 2-fold increase in EOCAD risk; none had a rare mutation involved in monogenic dyslipidemia or EOCAD.
Conclusions:
These results suggest a significant polygenic contribution in individuals presenting with EOCAD, which could be more prevalent than familial hypercholesterolemia. Determination of the polygenic risk component could be included in the diagnostic workup of patients with EOCAD.
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