Key result
Genetic liability to smoking significantly increased the risk of peripheral artery disease (OR 2.13), coronary artery disease (OR 1.48), and large-artery stroke (OR 1.40), independent of traditional risk factors.
Why the study?
Smoking is linked with atherosclerotic cardiovascular disease, but its relative contribution across CAD, PAD, and large-artery stroke is less well understood.
Does genetic liability to smoking increase the risk of coronary artery disease, peripheral artery disease, and large-artery stroke in primarily European-ancestry individuals?
Observational (n=462,690)
Mendelian Randomization
Yes
Does genetic liability to smoking increase the risk of coronary artery disease, peripheral artery disease, and large-artery stroke in primarily European-ancestry individuals?
Odds Ratio: 2.13 (95% CI 1.78–2.56)
p-value: p=3.6 x 10-16
Genetic liability to smoking is a strong, causal risk factor for CAD, PAD, and stroke, with the strongest effect observed for PAD, and this risk is independent of traditional cardiovascular risk factors.
Supports causality of smoking for PAD, CAD, and stroke; leaves open validation in diverse ancestries and intervention trials.
Importance Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood. Objective To determine the effect of smoking on risk of coronary artery disease, peripheral artery disease, and large-artery stroke. Design Mendelian randomization study using summary statistics from genome-wide associations of smoking (up to 462,690 individuals), coronary artery disease (up to 60,801 cases, 123,504 controls), peripheral artery disease (up to 24,009 cases, 150,983 controls), and large-artery stroke (up to 4,373 cases, 406,111 controls) Setting Population-based study of primarily European-ancestry individuals Participants Participants in genome-wide association studies of smoking, coronary artery disease, peripheral artery disease, and stroke. Exposures Genetic liability to smoking defined by lifetime smoking index: an integrated measure of smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and declining effect of smoking on health outcomes). Main Outcome Measure Risk of coronary artery disease, peripheral artery disease, and large-artery stroke. Results Genetic liability to smoking was associated with increased risk of PAD (OR 2.13; 95% CI 1.78-2.56; P = 3.6 × 10 −16 ), CAD (OR 1.48; 95% CI 1.25-1.75; P = 4.4 × 10 −6 ), and stroke (OR 1.4; 95% CI 1.02-1.92; P = 0.036). Risk of PAD in smokers was greater than risk of large-artery stroke (p difference = 0.025) or CAD (p difference = 0.0041). The effect of smoking on ASCVD remained independent from the effects of smoking on traditional cardiovascular risk factors. Conclusions and Relevance Genetic liability to smoking is a strong, causal risk factor for CAD, PAD, and stroke, although the effect of smoking is strongest for PAD. The effect of smoking is independent of traditional cardiovascular risk factors.
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Levin et al. (2020) conducted an observational in Atherosclerotic cardiovascular disease (CAD, PAD, large-artery stroke) (n=462,690). Genetic liability to smoking (lifetime smoking index) vs. Lower genetic liability to smoking was evaluated on Risk of peripheral artery disease (PAD) (OR 2.13, 95% CI 1.78-2.56, p=3.6 x 10-16). Genetic liability to smoking significantly increased the risk of peripheral artery disease (OR 2.13), coronary artery disease (OR 1.48), and large-artery stroke (OR 1.40), independent of traditional risk factors.
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