Michael G Levin1,2,3, Derek Klarin4,5, Themistocles L Assimes6,7,8, Matthew S Freiberg9,10,11, Erik Ingelsson7,8,12,13, Julie Lynch14,15, Pradeep Natarajan16,17,18,19, Christopher O'Donnell19, Daniel J Rader2,20,21, Philip S Tsao6,22, Kyong-Mi Chang2,3, Benjamin F Voight3,20,21,23, Scott M Damrauer3,24. 1. Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia. 2. Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia. 3. Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania. 4. Malcolm Randall VA Medical Center, Gainesville, Florida. 5. Department of Surgery, University of Florida, Gainesville. 6. Palo Alto VA Healthcare System, Palo Alto, California. 7. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California. 8. Stanford Cardiovascular Institute, Stanford University, Stanford, California. 9. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 10. Geriatric Research Education and Clinical Centers, Veterans Affairs Tennessee Valley Healthcare System, Nashville. 11. Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. 12. Stanford Diabetes Research Center, Stanford University, Stanford, California. 13. Now with GlaxoSmithKline, San Francisco, California. 14. Edith Nourse VA Medical Center, Bedford, Massachusetts. 15. VA Informatics and Computing Infrastructure, Salt Lake City, Utah. 16. Cardiovascular Research Center, Massachusetts General Hospital, Boston. 17. Broad Institute of Harvard and MIT, Cambridge, Massachusetts. 18. Department of Medicine, Harvard Medical School, Boston, Massachusetts. 19. VA Boston Healthcare System, Boston, Massachusetts. 20. Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia. 21. Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia. 22. Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Palo Alto, California. 23. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia. 24. Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia.
Abstract
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.
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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