Table 3. Total, Direct, and Indirect Effects of GRS50 on Incident CHD With Metabolic Mediators, Adjusted for Age at Baseline, Sex, and Smoking Status
EffectsGRS50 (High vs Low)GRS50 (High vs Low/Intermediate)
Hazard Ratio (95% CI)Proportion Explained (%) (95% CI)aAdditional Incident CHD Cases Per 100 000 Person‐Years at RiskbHazard Ratio (95% CI)Proportion Explained (%) (95% CI)aAdditional Incident CHD Cases Per 100 000 Person‐Years at Riskb
Total effect2.01 (1.76–2.30)100.0%469.31.53 (1.39–1.68)100.0%314.2
Direct effectc1.87 (1.64–2.14)89.3% (84.0–94.2%)424.71.45 (1.32–1.59)87.4% (80.9–92.7%)281.2
Indirect effect, combined1.08 (1.04–1.11)10.7% (5.8–16.0%)44.61.06 (1.03–1.08)12.6% (7.3–19.1%)33.0
Indirect effect, through systolic blood pressure and hypertension treatment1.02 (1.01–1.04)3.5% (1.0–5.9%)16.21.02 (1.01–1.03)4.2% (1.3–7.5%)11.9
Indirect effect, through apoA‐I1.01 (1.00–1.02)1.1% (−0.2% to 2.6%)5.31.01 (1.00–1.01)1.2% (−0.5% to 3.0%)3.6
Indirect effect, through apoB1.04 (1.03–1.06)6.0% (3.7–8.6%)22.31.04 (1.02–1.05)8.1% (5.5–11.8%)19.9
Indirect effect, through diabetes mellitus1.00 (0.99–1.02)0.2% (−1.6% to 2.7%)0.71.00 (0.98–1.01)−0.9% (−3.7% to 1.6%)−2.4
  • apoA‐I indicates apolipoprotein A‐I; apoB, apolipoprotein B; CHD, coronary heart disease; GRS50, 50‐variant genetic risk score.

  • a On ln(HR) scale.

  • b Estimates from additive hazards models with time‐independent effects.

  • c Effect of GRS50 not mediated by the 4 analyzed risk factors.