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Published on: August 9, 2024
Polygenic Risk and Coronary Artery Disease Severity
Alborz Sherafati1, Kristjan Norland1, Mohammadreza Naderian1
1Department of Cardiovascular Medicine (A.S., K.N., M.N., I.J.K.).
Insights
Genetic predisposition for coronary heart disease (CHD) is linked to coronary artery disease (CAD) severity. CAD severity significantly mediates the association between genetic risk and heart attacks, revealing a strong genetic overlap.
Area of Science:
- Cardiovascular Genetics
- Genomic Medicine
- Translational Cardiology
Background:
- Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes.
- A shared genetic etiology is likely for these cardiovascular phenotypes.
Purpose of the Study:
- To investigate the association of polygenic risk scores for coronary heart disease (PRS_CHD) with coronary artery disease (CAD) severity.
- To assess the joint impact of PRS_CHD and familial hypercholesterolemia (FH) variants on CAD severity.
- To explore the mediating role of CAD severity in the relationship between PRS_CHD and major adverse cardiovascular events.
Main Methods:
- Analysis of 6021 patients with coronary angiography, genotyping, and exome sequencing data.
- Calculation of polygenic risk scores for coronary heart disease (PRS_CHD).
- Mediation analyses to assess the role of CAD severity in linking genetic risk to clinical outcomes.
Main Results:
- A 1-SD increase in PRS_CHD was significantly associated with increased CAD severity, measured by the log Gensini score.
- Pathogenic variants in FH genes were associated with higher CAD severity, even after adjusting for PRS_CHD.
- PRS_CHD was associated with incident myocardial infarction, with CAD severity mediating 90% of this association.
Conclusions:
- Polygenic risk scores for coronary heart disease are associated with coronary artery disease severity.
- CAD severity substantially mediates the link between genetic predisposition and myocardial infarction, highlighting significant genetic overlap.
Background:
Coronary atherosclerotic burden and adverse coronary heart disease events are related phenotypes with likely shared genetic cause.
Methods:
We analyzed 6021 patients with available coronary angiography, genotyping, and exome sequencing data. We tested for associations of polygenic risk scores for coronary heart disease (PRSCHD) with multiple measures of coronary artery disease (CAD) severity. We assessed the joint associations of PRSCHD and pathogenic/likely pathogenic variants in 3 familial hypercholesterolemia genes, with CAD severity. We performed mediation analyses to explore whether CAD severity mediated the association of PRSCHD with prevalent coronary heart disease and incident myocardial infarction.
Results:
A 1-SD increase in PRSCHD was associated with multiple measures of CAD severity, including the log Gensini score (β, 0.31 [95% CI, 0.28-0.33]). Carrying a pathogenic/likely pathogenic familial hypercholesterolemia variant was associated with a higher log Gensini score after adjustment for PRSCHD (β, 0.21 [95% CI, 0.03-0.38]). A 1-SD increase in PRSCHD was associated with incident myocardial infarction over a mean follow-up of 9.2 years (hazard ratio, 1.20 [95% CI, 1.13-1.27]; P=5×10-10), and the Gensini score mediated 90% of this association.
Conclusions:
PRSCHD was associated with multiple measures of CAD severity. The association of PRSCHD with incident myocardial infarction was almost fully mediated by CAD severity, indicating a considerable genetic overlap between the 2 phenotypes.
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