Background:
Several risk factors for coronary artery disease (CAD) have been described, some of which are genetically determined. The use of a polygenic risk score (PRS) could improve CAD risk assessment, but predictive accuracy according to age and sex is not well established.
Methods:
A PRS
CAD
including the weighted effects of >1.14 million SNPs associated with CAD was calculated in UK Biobank (n=408 422), using LDpred. Cox regressions were performed, stratified by age quartiles and sex, for incident myocardial infarction (MI) and mortality, with a median follow-up of 11.0 years. Improvement in risk prediction of MI was assessed by comparing PRS
CAD
to the pooled cohort equation with categorical net reclassification index using a 2% threshold (NRI
0.02
) and continuous NRI (NRI
>0
).
Results:
From 7746 incident MI cases and 393 725 controls, hazard ratio for MI reached 1.53 (95% CI, 1.49–1.56;
P
=2.69×10
−296
) per SD increase of PRS
CAD
. PRS
CAD
was significantly associated with MI in both sexes, with a stronger association in men (interaction
P
=0.002), particularly in those aged between 40 and 51 years (hazard ratio, 2.00 [95% CI, 1.86–2.16],
P
=1.93×10
−72
). This group showed the highest reclassification improvement, mainly driven by the up-classification of cases (NRI
0.02
, 0.199 [95% CI, 0.157–0.248] and NRI
>0
, 0.602 [95% CI, 0.525–0.683]). From 23 982 deaths, hazard ratio for mortality was 1.08 (95% CI, 1.06–1.09;
P
=5.46×10
−30
) per SD increase of PRS
CAD
, with a stronger association in men (interaction
P
=1.60×10
−6
).
Conclusions:
Our PRS
CAD
predicts MI incidence and all-cause mortality, especially in men aged between 40 and 51 years. PRS could optimize the identification and management of individuals at risk for CAD.
Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death
