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Only a minority of heavy drinkers acquires AH and severity varies among affected individuals, suggesting a genetic basis for the susceptibility to and severity of AH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A cohort consisting of 211 patients with AH and 176 heavy drinking controls was genotyped for five variants in five candidate genes that have been associated with chronic liver diseases: rs738409 in patatin\u2010like phospholipase domain\u2010containing protein 3 (<jats:italic>PNPLA3<\/jats:italic>), rs72613567 in hydroxysteroid 17\u2010beta dehydrogenase 13 (<jats:italic>HSD17B13<\/jats:italic>), rs58542926 in transmembrane 6 superfamily member 2 (<jats:italic>TM6SF2<\/jats:italic>), rs641738 in membrane bound <jats:italic>O<\/jats:italic>\u2010acyltransferase domain containing 7 (<jats:italic>MBOAT7<\/jats:italic>), and a copy number variant in the haptoglobin (<jats:italic>HP<\/jats:italic>) gene. We tested the effects of individual variants and the combined\/interacting effects of variants on AH risk and severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found significant associations between AH risk and the risk alleles of rs738409 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0081) and <jats:italic>HP<\/jats:italic> (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0371), but not rs72613567 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.3132), rs58542926 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.2180), or rs641738 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.7630), after adjusting for patient's age and sex. A multiple regression model indicated that <jats:italic>PNPLA3<\/jats:italic> rs738409:G [OR\u00a0=\u00a01.59 (95% CI: 1.15\u20132.22), <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0055] and <jats:italic>HP<\/jats:italic>*2 [OR\u00a0=\u00a01.38 (95% CI: 1.04\u20131.82), <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0245], when combined and adjusted for age and sex also had a large influence on AH risk among heavy drinkers. In the entire cohort, variants in <jats:italic>PNPLA3<\/jats:italic> and <jats:italic>HP<\/jats:italic> were associated with increased total bilirubin and Model for End\u2010stage Liver Disease (MELD) score, both measures of AH severity. The <jats:italic>HSD17B13<\/jats:italic> rs72613567:AA allele was not found to reduce risk of AH in patients carrying the G allele of <jats:italic>PNPLA3<\/jats:italic> rs738409 (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0921).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>PNPLA3<\/jats:italic> and <jats:italic>HP<\/jats:italic> genetic variants increase AH risk and are associated with total bilirubin and MELD score, surrogates of AH severity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14581","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T10:19:06Z","timestamp":1613989146000},"page":"709-719","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of candidate gene variants in modulating the risk and severity of alcoholic hepatitis"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-8844","authenticated-orcid":false,"given":"James J.","family":"Beaudoin","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics Eshelman School of Pharmacy University of North Carolina  Chapel Hill NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8445-3765","authenticated-orcid":false,"given":"Tiebing","family":"Liang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Indiana University School of Medicine and Richard M. Fairbanks School of Public Health  Indianapolis IN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bubu A.","family":"Banini","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University  Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijay H.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Mayo Clinic  Rochester MN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun J.","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University  Richmond VA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naga P.","family":"Chalasani","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine  Indianapolis IN USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2056-4909","authenticated-orcid":false,"given":"Samer","family":"Gawrieh","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine  Indianapolis IN 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