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Mendelian randomization (MR) studies suggest that these associations are due to confounding. We present observed and genetically proxied associations between alcohol consumption and the incidence of CHD and T2D among African Americans (AA), European Americans (EA), and Hispanic Americans (HA) from the Million Veteran Program.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted two retrospective, nested case\u2013control studies of 33,053 CHD and 28,278 T2D cases matched to five controls each at the time of the event (index date). We used the Alcohol Use Disorders Identification Test\u2013Consumption (AUDIT\u2010C) score closest in time prior to the index date to estimate alcohol exposure. Models were adjusted for smoking, body mass index (BMI), chronic kidney disease, rheumatoid arthritis, and the use of statins or antihypertensive medications. MR analyses used either a single variant in <jats:italic>ADH1B<\/jats:italic> or a genetic score (GS) as instrumental variables.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Observational analysis showed a U\u2010shaped association of alcohol consumption with CHD and T2D risk. However, in MR analyses, neither <jats:italic>ADH1B<\/jats:italic> genotype\u2010predicted (in 36,465 AAs, 146,464 EAs, and 11,342 HAs) nor GS\u2010predicted (in EAs) alcohol consumption was associated with CHD risk. Similarly, T2D was not associated with alcohol consumption predicted either by <jats:italic>ADH1B<\/jats:italic> genotype (in 42,008 AAs, 109,351 EAs, and 13,538 HAs) or GS (in EAs). Multivariable MR analyses that adjusted for the effects of blood pressure and smoking also showed no association between alcohol consumption and cardiometabolic diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We replicate prior observational studies that show a U\u2010shaped association between alcohol consumption and cardiometabolic diseases, but MR findings show no causal association between these traits. This is largely consistent with previous MR analyses in EAs and expands the literature by providing similar findings in AA and HA populations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15445","type":"journal-article","created":{"date-parts":[[2024,11,24]],"date-time":"2024-11-24T15:01:08Z","timestamp":1732460468000},"page":"2256-2268","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Mendelian randomization study of alcohol use and cardiometabolic disease risk in a multi\u2010ancestry population from the Million Veteran Program"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8820-2659","authenticated-orcid":false,"given":"Rachel L.","family":"Kember","sequence":"first","affiliation":[{"name":"Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"},{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0139-5502","authenticated-orcid":false,"given":"Amy C.","family":"Justice","sequence":"additional","affiliation":[{"name":"Veterans Affairs Connecticut Healthcare System  West Haven Connecticut USA"},{"name":"Department of Internal Medicine Yale School of Medicine  New Haven Connecticut USA"},{"name":"Yale School of Public Health  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Million Veteran Program","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Themistocles L.","family":"Assimes","sequence":"additional","affiliation":[{"name":"VA Palo Alto Health Care System  Palo Alto California USA"},{"name":"Department of Medicine Stanford University  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-0450","authenticated-orcid":false,"given":"Henry R.","family":"Kranzler","sequence":"additional","affiliation":[{"name":"Crescenz Veterans Affairs Medical Center  Philadelphia Pennsylvania USA"},{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,24]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.160.7.1025"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15393"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc09\u20100227"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.3849"},{"key":"e_1_2_8_6_1","first-page":"597","article-title":"Implementation of evidence\u2010based 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