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Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study
Michael G Levin1,2,3, Derek Klarin4,5, Themistocles L Assimes6,7,8
1Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia.
Insights
Genetic predisposition to smoking significantly increases the risk of peripheral artery disease (PAD), coronary artery disease (CAD), and stroke. The strongest association was observed between genetic liability to smoking and PAD, independent of traditional risk factors.
Area of Science:
- Cardiovascular Genetics
- Epidemiology
- Public Health
Background:
- Smoking is a known risk factor for atherosclerotic cardiovascular disease (ASCVD).
- The specific contributions of smoking to different ASCVD subtypes, including coronary artery disease (CAD), peripheral artery disease (PAD), and large-artery stroke, require further elucidation.
Purpose of the Study:
- To investigate the association between genetic liability to smoking and the risk of developing CAD, PAD, and large-artery stroke.
- To compare the relative risk of these ASCVD subtypes conferred by genetic smoking liability.
Main Methods:
- A Mendelian randomization study design was employed.
- Utilized summary statistics from large-scale genome-wide association studies (GWAS) including UK Biobank, Coronary Artery Disease Genome Wide Replication and Meta-analysis, Coronary Artery Disease Genetics Consortium, VA Million Veteran Program, and MEGASTROKE.
- Analyzed genetic variants associated with lifetime smoking index as a proxy for genetic liability to smoking.
Main Results:
- Genetic liability to smoking was significantly associated with an increased risk of PAD (OR, 2.13), CAD (OR, 1.48), and stroke (OR, 1.40).
- The risk was notably higher for PAD compared to large-artery stroke and CAD.
- These associations remained significant even after accounting for traditional cardiovascular risk factors.
Conclusions:
- Genetic liability to smoking is a substantial risk factor for CAD, PAD, and stroke.
- Peripheral artery disease (PAD) exhibits the strongest association with genetic predisposition to smoking among the studied atherosclerotic cardiovascular diseases.
- The link between smoking liability and ASCVD is independent of established cardiovascular risk factors, highlighting a direct genetic pathway.
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 association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke.
Design, Setting, And Participants:
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.
Exposures:
Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index).
Main Outcomes And Measures:
Risk (odds ratios [ORs]) of CAD, PAD, 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, 1.40; 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.
Conclusions And Relevance:
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.
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