{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:21:34Z","timestamp":1791390094668,"version":"4.3.3"},"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"National Institutes of Health, Division of Intramural Clinical and Biological Research","award":["ZIA-AA000242"],"award-info":[{"award-number":["ZIA-AA000242"]}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alcohol consumption and smoking, 2 major risk factors for cardiovascular disease (CVD), often occur together. The objective of this study is to use a wide range of CVD risk factors and outcomes to evaluate potential total and direct causal roles of alcohol and tobacco use on CVD risk factors and events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      Using large publicly available genome-wide association studies (GWASs) (results from more than 1.2 million combined study participants) of predominantly European ancestry, we conducted 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) to simultaneously assess the independent impact of alcohol consumption and smoking on a wide range of CVD risk factors and outcomes. Multiple sensitivity analyses, including complementary Mendelian randomization (MR) methods, and secondary alcohol consumption and smoking datasets were used. SVMR showed genetic predisposition for alcohol consumption to be associated with CVD risk factors, including high-density lipoprotein cholesterol (HDL-C) (beta 0.40, 95% confidence interval (CI), 0.04\u20130.47,\n                      <jats:italic>P<\/jats:italic>\n                      value = 1.72 \u00d7 10\n                      <jats:sup>\u221228<\/jats:sup>\n                      ), triglycerides (TRG) (beta \u22120.23, 95% CI, \u22120.30, \u22120.15,\n                      <jats:italic>P<\/jats:italic>\n                      value = 4.69 \u00d7 10\n                      <jats:sup>\u221210<\/jats:sup>\n                      ), automated systolic blood pressure (BP) measurement (beta 0.11, 95% CI, 0.03\u20130.18,\n                      <jats:italic>P<\/jats:italic>\n                      value = 4.72 \u00d7 10\n                      <jats:sup>\u22123<\/jats:sup>\n                      ), and automated diastolic BP measurement (beta 0.09, 95% CI, 0.03\u20130.16,\n                      <jats:italic>P<\/jats:italic>\n                      value = 5.24 \u00d7 10\n                      <jats:sup>\u22123<\/jats:sup>\n                      ). Conversely, genetically predicted smoking was associated with increased TRG (beta 0.097, 95% CI, 0.014\u20130.027,\n                      <jats:italic>P<\/jats:italic>\n                      value = 6.59 \u00d7 10\n                      <jats:sup>\u221212<\/jats:sup>\n                      ). Alcohol consumption was also associated with increased myocardial infarction (MI) and coronary heart disease (CHD) risks (MI odds ratio (OR) = 1.24, 95% CI, 1.03\u20131.50,\n                      <jats:italic>P<\/jats:italic>\n                      value = 0.02; CHD OR = 1.21, 95% CI, 1.01\u20131.45,\n                      <jats:italic>P<\/jats:italic>\n                      value = 0.04); however, its impact was attenuated in MVMR adjusting for smoking. Conversely, alcohol maintained an association with coronary atherosclerosis (OR 1.02, 95% CI, 1.01\u20131.03,\n                      <jats:italic>P<\/jats:italic>\n                      value = 5.56 \u00d7 10\n                      <jats:sup>\u22124<\/jats:sup>\n                      ). In comparison, after adjusting for alcohol consumption, smoking retained its association with several CVD outcomes including MI (OR = 1.84, 95% CI, 1.43, 2.37,\n                      <jats:italic>P<\/jats:italic>\n                      value = 2.0 \u00d7 10\n                      <jats:sup>\u22126<\/jats:sup>\n                      ), CHD (OR = 1.64, 95% CI, 1.28\u20132.09,\n                      <jats:italic>P<\/jats:italic>\n                      value = 8.07 \u00d7 10\n                      <jats:sup>\u22125<\/jats:sup>\n                      ), heart failure (HF) (OR = 1.61, 95% CI, 1.32\u20131.95,\n                      <jats:italic>P<\/jats:italic>\n                      value = 1.9 \u00d7 10\n                      <jats:sup>\u22126<\/jats:sup>\n                      ), and large artery atherosclerosis (OR = 2.4, 95% CI, 1.41\u20134.07,\n                      <jats:italic>P<\/jats:italic>\n                      value = 0.003). Notably, using the FinnGen cohort data, we were able to replicate the association between smoking and several CVD outcomes including MI (OR = 1.77, 95% CI, 1.10\u20132.84,\n                      <jats:italic>P<\/jats:italic>\n                      value = 0.02), HF (OR = 1.67, 95% CI, 1.14\u20132.46,\n                      <jats:italic>P<\/jats:italic>\n                      value = 0.008), and peripheral artery disease (PAD) (OR = 2.35, 95% CI, 1.38\u20134.01,\n                      <jats:italic>P<\/jats:italic>\n                      value = 0.002). The main limitations of this study include possible bias from unmeasured confounders, inability of summary-level MR to investigate a potentially nonlinear relationship between alcohol consumption and CVD risk, and the generalizability of the UK Biobank (UKB) to other populations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Evaluating the widest range of CVD risk factors and outcomes of any alcohol consumption or smoking MR study to date, we failed to find a cardioprotective impact of genetically predicted alcohol consumption on CVD outcomes. However, alcohol was associated with and increased HDL-C, decreased TRG, and increased BP, which may indicate pathways through impact CVD risk, warranting further study. We found smoking to be a risk factor for many CVDs even after adjusting for alcohol. While future studies incorporating alcohol consumption patterns are necessary, our data suggest causal inference between alcohol, smoking, and CVD risk, further supporting that lifestyle modifications might be able to reduce overall CVD risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1003410","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T13:33:47Z","timestamp":1607088827000},"page":"e1003410","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":184,"title":["Evaluating the relationship between alcohol consumption, tobacco use, and cardiovascular disease: A multivariable Mendelian randomization study"],"prefix":"10.1371","volume":"17","author":[{"given":"Daniel B.","family":"Rosoff","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-8314","authenticated-orcid":true,"given":"George","family":"Davey Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nehal","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni-Kim","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0480-7755","authenticated-orcid":true,"given":"Falk W.","family":"Lohoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"issue":"14","key":"pmed.1003410.ref001","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1056\/NEJMoa1406656","article-title":"Demographic and Epidemiologic Drivers of Global Cardiovascular Mortality","volume":"372","author":"GA Roth","year":"2015","journal-title":"N Engl J Med"},{"key":"pmed.1003410.ref002","volume-title":"Global Progress Report on Implementation of the WHO Framework Convention on Tobacco Control","author":"World Health Organization","year":"2018"},{"key":"pmed.1003410.ref003","first-page":"286","volume-title":"Global Status Report on Alcohol and Health","author":"World Health Organization","year":"2011"},{"key":"pmed.1003410.ref004","unstructured":"Ezzati M, Hoorn SV, Lopez AD, Danaei G, Rodgers A, Mathers CD, et al. 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