Abstract
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. To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke. Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462 690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60 801 cases, 123 504 controls), PAD (VA Million Veteran Program; up to 24 009 cases, 150 983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406 111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020. Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index). Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke. 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, 1.40; 95% CI, 1.02-1.92; P = .04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19; P = .02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84; P = .004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors. In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.
Highlights
Atherosclerotic cardiovascular disease (ASCVD) can affect numerous vascular beds throughout the body, with clinical manifestations including coronary artery disease (CAD), stroke, and peripheral artery disease (PAD)
In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, the estimated association was strongest between smoking and PAD
Key Points Question Are there differential associations between genetic liability to smoking and atherosclerotic cardiovascular disease (ASCVD) outcomes?. In this mendelian randomization study including summary data for more than 1 million individuals, genetic liability to smoking was associated with increased risk of ASCVD, with the largest association with peripheral artery disease, independent from other cardiovascular risk factors
Summary
Atherosclerotic cardiovascular disease (ASCVD) can affect numerous vascular beds throughout the body, with clinical manifestations including coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Observational studies have examined these ASCVD outcomes together, with a recent study by Ding et al finding the strongest association between smoking and incident PAD compared with CAD or stroke.[1,2,3,4] Observational study designs may be limited, by modest overall sample size, measurement error, and risk of residual confounding.[5]. A number of studies during the last several decades have identified detrimental effects of smoking on traditional cardiovascular risk factors, including blood pressure, lipids, and diabetes.[6,7] Smoking has independent effects on inflammation, endothelial function, and platelet aggregation.[6] Despite the clear observational links between smoking and atherosclerosis, whether the effect of smoking on ASCVD is primarily mediated through correlated alterations of traditional cardiovascular risk factors, or operates via independent mechanisms is less clear. Because the detrimental effects of smoking may persist for decades,[4] clarifying the basis of the smokingatherosclerosis relationship could enable more targeted risk-reduction strategies among both current and former smokers and identify novel treatment strategies for those at highest risk of ASCVD
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