{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T12:08:09Z","timestamp":1785326889850,"version":"3.55.0"},"reference-count":73,"publisher":"American Society for Clinical Investigation","issue":"8","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":43,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["1ZIAAA000440-02"],"award-info":[{"award-number":["1ZIAAA000440-02"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012304","name":"Johns Hopkins University School of Medicine","doi-asserted-by":"crossref","award":["R24AA025017"],"award-info":[{"award-number":["R24AA025017"]}],"id":[{"id":"10.13039\/100012304","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver disease (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express allograft inflammatory factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not, based on DSM-IV\/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the\n                      <jats:italic>AIF1<\/jats:italic>\n                      promoter single-nucleotide polymorphism (SNP) (rs3132451;\n                      <jats:italic>C\/C<\/jats:italic>\n                      ,\n                      <jats:italic>C\/G<\/jats:italic>\n                      ,\n                      <jats:italic>G\/G<\/jats:italic>\n                      ) on liver function markers and immune cell profiles.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      <jats:italic>AIF1<\/jats:italic>\n                      transcript levels were genotype dependent:\n                      <jats:italic>C\/C<\/jats:italic>\n                      homozygotes expressed 5.2% of the levels observed in\n                      <jats:italic>G\/G<\/jats:italic>\n                      individuals, while\n                      <jats:italic>C\/G<\/jats:italic>\n                      heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the\n                      <jats:italic>G\/G<\/jats:italic>\n                      genotype is highly prevalent, present in about 70% of patients. Among chronic alcohol users,\n                      <jats:italic>G\/G<\/jats:italic>\n                      individuals exhibited elevated markers of liver injury and a more than 3-fold increase in hepatic immune cells, including infiltrating AIF1\n                      <jats:sup>+<\/jats:sup>\n                      macrophages and neutrophils. Despite similar durations of alcohol misuse,\n                      <jats:italic>G\/G<\/jats:italic>\n                      individuals had higher Model for End-Stage Liver Disease scores compared with\n                      <jats:italic>C\/G<\/jats:italic>\n                      individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in\n                      <jats:italic>G\/G<\/jats:italic>\n                      males even after alcohol abstinence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>\n                      These findings suggest that functional genetic variation in\n                      <jats:italic>AIF1<\/jats:italic>\n                      may contribute to the severity and persistence of ALD.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>TRIAL REGISTRATION<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT02231840.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Research support was provided from the National Institute on Alcohol Abuse and Alcoholism of the NIH under grants 1ZIAAA000440-02 and R24AA025017.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.198209","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T17:10:58Z","timestamp":1773681058000},"source":"Crossref","is-referenced-by-count":1,"title":["Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use"],"prefix":"10.1172","volume":"11","author":[{"given":"Priscila C.","family":"Antonello","sequence":"first","affiliation":[{"name":"Section on Neural Circuits,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin A.","family":"Hodgkinson","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7485-762X","authenticated-orcid":true,"given":"Dechun","family":"Feng","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl","family":"Marietta","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baskar","family":"Mohana Krishnan","sequence":"additional","affiliation":[{"name":"Section on Neural Circuits,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Parra","sequence":"additional","affiliation":[{"name":"Transplant Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoli","family":"Sun","sequence":"additional","affiliation":[{"name":"Transplant Biology Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1724-5405","authenticated-orcid":true,"given":"David","family":"Goldman","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle W.","family":"Antoine","sequence":"additional","affiliation":[{"name":"Section on Neural Circuits,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31775-1"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI176345"},{"key":"B3"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2018.10.023"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.09.002"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2013.07.008"},{"key":"B7","unstructured":"The Human Protein Atlas. 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