{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:33:23Z","timestamp":1789392803290,"version":"build-2803163510"},"reference-count":37,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2017,11,6]],"date-time":"2017-11-06T00:00:00Z","timestamp":1509926400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2017,11,6]],"date-time":"2017-11-06T00:00:00Z","timestamp":1509926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:p>The interferon (IFN) lambda 3\/4 (IFNL3\/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN\u2010stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT&gt;\u03b4G, rs12979860 C&gt;T, and patatin\u2010like phospholipase\u20103 rs738409 C&gt;G polymorphisms were genotyped; and IFN\u2010stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3\u2010F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15\u20102.31;<jats:italic toggle=\"yes\">P<\/jats:italic>= 0.005) and with severe (grade 2\u20103) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14\u20101.88;<jats:italic toggle=\"yes\">P<\/jats:italic>= 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (<jats:italic toggle=\"yes\">P<\/jats:italic>&lt; 0.05). IFN\u2010stimulated genes were hypo\u2010expressed in the liver of patients carrying the IFNL4 rs368234815 TT\/TT genotype (<jats:italic toggle=\"yes\">P<\/jats:italic>&lt; 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (<jats:italic toggle=\"yes\">R<\/jats:italic><jats:sup>2<\/jats:sup>= 0.87).<jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (H<jats:sc>epatology<\/jats:sc>2017;66:1885\u20131893)<\/jats:p>","DOI":"10.1002\/hep.29395","type":"journal-article","created":{"date-parts":[[2017,7,25]],"date-time":"2017-07-25T02:14:55Z","timestamp":1500948895000},"page":"1885-1893","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":83,"title":["Interferon lambda 4 rs368234815 TT&gt;\u03b4G variant is associated with liver damage in patients with nonalcoholic fatty liver disease"],"prefix":"10.1097","volume":"66","author":[{"given":"Salvatore","family":"Petta","sequence":"first","affiliation":[{"name":"Sezione di Gastroenterologia e Epatologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8909-0345","authenticated-orcid":false,"given":"Luca","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Section of Internal Medicine, Universit\u00e0 degli Studi,Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Tuttolomondo","sequence":"additional","affiliation":[{"name":"Sezione di Medicina Interna e Cardioangiologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Dongiovanni","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Section of Internal Medicine, Universit\u00e0 degli Studi,Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria Maria","family":"Pipitone","sequence":"additional","affiliation":[{"name":"Sezione di Gastroenterologia e Epatologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calogero","family":"Camm\u00e0","sequence":"additional","affiliation":[{"name":"Sezione di Gastroenterologia e Epatologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Cabibi","sequence":"additional","affiliation":[{"name":"Cattedra di Anatomia Patologica,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Di Marco","sequence":"additional","affiliation":[{"name":"Sezione di Gastroenterologia e Epatologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Ludovica","family":"Fracanzani","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Section of Internal Medicine, Universit\u00e0 degli Studi,Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Badiali","sequence":"additional","affiliation":[{"name":"Department of Surgery,Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerio","family":"Nobili","sequence":"additional","affiliation":[{"name":"Hepatometabolic Unit,Bambino Ges\u00f9 Children's Hospital,Rome,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Fargion","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Section of Internal Medicine, Universit\u00e0 degli Studi,Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Grimaudo","sequence":"additional","affiliation":[{"name":"Sezione di Gastroenterologia e Epatologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Crax\u00ec","sequence":"additional","affiliation":[{"name":"Sezione di Gastroenterologia e Epatologia, DiBiMIS,University of Palermo,Palermo,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,11,6]]},"reference":[{"key":"hep29395-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1002\/hep.28677","article-title":"Prevalence of chronic liver disease and cirrhosis by underlying cause in understudied ethnic groups: the multiethnic cohort","volume":"64","year":"2016","journal-title":"Hepatology"},{"key":"hep29395-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease\u2014meta\u2010analytic assessment of prevalence, incidence, and 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