{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:02:08Z","timestamp":1792465328166,"version":"4.5.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T00:00:00Z","timestamp":1650499200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>It is unclear whether rs738409 (p.I148M) missense variant in patatin\u2010like phospholipase domain\u2010containing 3 rs738409 promotes fibrosis development by triggering specific fibrogenic pathways or by creating an unfavorable microenvironment by promoting steatosis, inflammation, and ultimately fibrosis. We tested the hypothesis that intermediate histologic traits, including steatosis, lobular and portal inflammation, and ballooning may determine the effect of rs738409 on liver fibrosis among individuals with biopsy\u2010proven NAFLD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      Causal mediation models including multiple mediators in parallel or sequentially were performed to examine the effect of rs738409, by decomposing its total effect on fibrosis severity into direct and indirect effects, mediated by histology traits in 1153 non\u2010Hispanic White patients. Total effect of rs738409 on fibrosis was\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      \u00a0=\u00a00.19 (95% CI: 0.09\u20130.29). The direct effect of rs738409 on fibrosis after removing mediators\u2019 effects was\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      \u00a0=\u00a00.09 (95% CI: 0.01\u20130.17) and the indirect effect of rs738409 on fibrosis through all mediators' effects were\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      \u00a0=\u00a00.010 (95% CI: 0.04\u20130.15). Among all mediators, the greatest estimated effect size was displayed by portal inflammation (\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      \u00a0=\u00a00.09, 95% CI: 0.05\u20130.12). Among different sequential combinations of histology traits, the path including lobular inflammation followed by ballooning degeneration displayed the most significant indirect effect (\n                      <jats:italic toggle=\"yes\">\u03b2<\/jats:italic>\n                      \u00a0=\u00a00.023, 95% CI: 0.011\u20130.037). Mediation analysis in a separate group of 404 individuals with biopsy\u2010proven NAFLD from other races and ethnicity showed similar results.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In NAFLD, nearly half of the total effect of the rs738409 G allele on fibrosis severity could be explained by a direct pathway, suggesting that rs738409 may promote fibrosis development by activating specific fibrogenic pathways. A large proportion of the indirect effect of rs738409 on fibrosis severity is mediated through portal inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32491","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T14:55:32Z","timestamp":1648565732000},"page":"1482-1494","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":30,"title":["PNPLA3 rs738409 and risk of fibrosis in NAFLD: Exploring mediation pathways through intermediate histological features"],"prefix":"10.1097","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1435-4013","authenticated-orcid":false,"given":"Eduardo","family":"Vilar\u2010Gomez","sequence":"first","affiliation":[{"name":"12250,Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,Indiana,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8234-4058","authenticated-orcid":false,"given":"Carlos J.","family":"Pirola","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Biology of Complex Diseases and Department of Clinical and Molecular Hepatology,Institute of Medical Research,University of Buenos Aires\u2010National Scientific and Technical Research Council,Ciudad Autonoma de Buenos Aires,Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5929-5470","authenticated-orcid":false,"given":"Silvia","family":"Sookoian","sequence":"additional","affiliation":[{"name":"Molecular Genetics and Biology of Complex Diseases and Department of Clinical and Molecular Hepatology,Institute of Medical Research,University of Buenos Aires\u2010National Scientific and Technical Research Council,Ciudad Autonoma de Buenos Aires,Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Johns Hopkins Bloomberg School of Public Health,Baltimore,Maryland,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiebing","family":"Liang","sequence":"additional","affiliation":[{"name":"12250,Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,Indiana,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-3178","authenticated-orcid":false,"given":"Naga","family":"Chalasani","sequence":"additional","affiliation":[{"name":"12250,Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,Indiana,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,4,21]]},"reference":[{"key":"hep32491-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1038\/ng.257","article-title":"Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease","volume":"40","year":"2008","journal-title":"Nat Genet"},{"key":"hep32491-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1194\/jlr.P900013-JLR200","article-title":"A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity","volume":"50","year":"2009","journal-title":"J Lipid Res"},{"key":"hep32491-bib-0003-20241017","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1002\/hep.23768","article-title":"PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep32491-bib-0004-20241017","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1002\/hep.23759","article-title":"The association of genetic variability in patatin\u2010like phospholipase domain\u2010containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep32491-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1002\/hep.24283","article-title":"Meta\u2010analysis of the influence of I148M variant of patatin\u2010like phospholipase domain containing 3 gene (PNPLA3) on the susceptibility and histological severity of nonalcoholic fatty liver disease","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep32491-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1002\/hep.31032","article-title":"Patatin\u2010like phospholipase domain\u2010containing protein 3 I148M and liver fat and fibrosis scores predict liver disease mortality in the U.S. population","volume":"71","year":"2020","journal-title":"Hepatology"},{"key":"hep32491-bib-0007-20241017","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jhep.2016.03.011","article-title":"PNPLA3 gene in liver diseases","volume":"65","year":"2016","journal-title":"J Hepatol"},{"key":"hep32491-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"6706","DOI":"10.1074\/jbc.M109.064501","article-title":"A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis","volume":"285","year":"2010","journal-title":"J Biol Chem"},{"key":"hep32491-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.cmet.2012.04.008","article-title":"Adiponutrin functions as a nutritionally regulated lysophosphatidic acid acyltransferase","volume":"15","year":"2012","journal-title":"Cell Metab"},{"key":"hep32491-bib-0010-20241017","doi-asserted-by":"crossref","first-page":"37085","DOI":"10.1074\/jbc.M111.290114","article-title":"Expression and characterization of a PNPLA3 protein isoform (I148M) associated with nonalcoholic fatty liver disease","volume":"286","year":"2011","journal-title":"J Biol Chem"},{"key":"hep32491-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"4130","DOI":"10.1172\/JCI65179","article-title":"Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis","volume":"122","year":"2012","journal-title":"J Clin Invest"},{"key":"hep32491-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1002\/hep.27242","article-title":"Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep32491-bib-0013-20241017","first-page":"26","article-title":"Transcriptional regulation of PNPLA3 and its impact on susceptibility to nonalcoholic fatty liver Disease (NAFLD) in humans","volume":"9","year":"2016","journal-title":"Aging (Albany NY)"},{"key":"hep32491-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/hep.29273","article-title":"The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation","volume":"66","year":"2017","journal-title":"Hepatology"},{"key":"hep32491-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"9521","DOI":"10.1073\/pnas.1901974116","article-title":"Accumulation of PNPLA3 on lipid droplets is the basis of associated hepatic steatosis","volume":"116","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"hep32491-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1056\/NEJMoa2029349","article-title":"Prospective study of outcomes in adults with nonalcoholic fatty liver disease","volume":"385","year":"2021","journal-title":"N Engl J Med"},{"key":"hep32491-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.gastro.2015.04.043","article-title":"Liver fibrosis, but no other histologic features, is associated with long\u2010term outcomes of patients with nonalcoholic fatty liver disease","volume":"149","year":"2015","journal-title":"Gastroenterology"},{"key":"hep32491-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1053\/j.gastro.2018.04.034","article-title":"Fibrosis severity as a determinant of cause\u2010specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi\u2010national cohort study","volume":"155","year":"2018","journal-title":"Gastroenterology"},{"key":"hep32491-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S0016-5085(99)70506-8","article-title":"Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity","volume":"116","year":"1999","journal-title":"Gastroenterology"},{"key":"hep32491-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1002\/hep.510300604","article-title":"Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis","volume":"30","year":"1999","journal-title":"Hepatology"},{"key":"hep32491-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/hep.22724","article-title":"Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD\u2014clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep32491-bib-0022-20241017","article-title":"The protection conferred by HSD17B13 rs72613567 polymorphism on risk of steatohepatitis and fibrosis may be limited to selected subgroups of patients with NAFLD","volume":"12","year":"2021","journal-title":"Clin Transl Gastroenterol"},{"key":"hep32491-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1053\/j.gastro.2020.05.054","article-title":"ADH1B\u22172 is associated with reduced severity of nonalcoholic fatty liver disease in adults, independent of alcohol consumption","volume":"159","year":"2020","journal-title":"Gastroenterology"},{"key":"hep32491-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S0140-6736(14)61933-4","article-title":"Farnesoid X nuclear receptor ligand obeticholic acid for non\u2010cirrhotic, non\u2010alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo\u2010controlled trial","volume":"385","year":"2015","journal-title":"Lancet"},{"key":"hep32491-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1002\/hep.23784","article-title":"Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep32491-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","article-title":"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis","volume":"362","year":"2010","journal-title":"N Engl J Med"},{"key":"hep32491-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","year":"2005","journal-title":"Hepatology"},{"key":"hep32491-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1002\/hep.24127","article-title":"Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep32491-bib-0030-20241017","first-page":"9","article-title":"A study of effects of multicollinearity in the multivariable analysis","volume":"4","year":"2014","journal-title":"Int J Appl Sci Technol"},{"key":"hep32491-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1146\/annurev-publhealth-032315-021402","article-title":"Mediation analysis: a practitioner's guide","volume":"37","year":"2016","journal-title":"Annu Rev Public Health"},{"key":"hep32491-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"879","DOI":"10.3758\/BRM.40.3.879","article-title":"Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models","volume":"40","year":"2008","journal-title":"Behav Res Methods"},{"key":"hep32491-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1177\/1948550617715068","article-title":"Determining power and sample size for simple and complex mediation models","volume":"8","year":"2017","journal-title":"Soc Psychol Pers Sci"},{"key":"hep32491-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.jhep.2008.01.016","article-title":"Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non\u2010alcoholic fatty liver disease","volume":"48","year":"2008","journal-title":"J Hepatol"},{"key":"hep32491-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1136\/jcp.2010.079145","article-title":"Portal inflammation is associated with advanced histological changes in alcoholic and non\u2010alcoholic fatty liver disease","volume":"63","year":"2010","journal-title":"J Clin Pathol"},{"key":"hep32491-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1002\/hep.26072","article-title":"Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause?","volume":"57","year":"2013","journal-title":"Hepatology"},{"key":"hep32491-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"4077","DOI":"10.1093\/hmg\/ddu121","article-title":"PNPLA3 has retinyl\u2010palmitate lipase activity in human hepatic stellate cells","volume":"23","year":"2014","journal-title":"Hum Mol Genet"},{"key":"hep32491-bib-0039-20241017","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.3945\/jn.115.210633","article-title":"PNPLA3 I148M variant influences circulating retinol in adults with nonalcoholic fatty liver disease or obesity","volume":"145","year":"2015","journal-title":"J Nutr"},{"key":"hep32491-bib-0040-20241017","doi-asserted-by":"crossref","first-page":"E1568","DOI":"10.1210\/jc.2015-2978","article-title":"The genetic variant I148M in PNPLA3 is associated with increased hepatic retinyl\u2010palmitate storage in humans","volume":"100","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"hep32491-bib-0041-20241017","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1002\/hep.29041","article-title":"The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells","volume":"65","year":"2017","journal-title":"Hepatology"},{"key":"hep32491-bib-0042-20241017","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1002\/hep.23622","article-title":"Homozygosity for the patatin\u2010like phospholipase\u20103\/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease","volume":"51","year":"2010","journal-title":"Hepatology"},{"key":"hep32491-bib-0043-20241017","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1016\/j.cgh.2020.09.009","article-title":"PNPLA3 rs738409 C>G variant predicts fibrosis progression by noninvasive tools in nonalcoholic fatty liver disease","volume":"19","year":"2021","journal-title":"Clin Gastroenterol Hepatol"},{"key":"hep32491-bib-0044-20241017","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/hep.24123","article-title":"Patatin\u2010like phospholipase domain\u2010containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep32491-bib-0045-20241017","first-page":"158674","article-title":"Retinoids in health and disease: a role for hepatic stellate cells in affecting retinoid levels","volume":"1865","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"issue":"Suppl 2","key":"hep32491-bib-0046-20241017","first-page":"75","article-title":"Retinoic acids and hepatic stellate cells in liver disease","volume":"27","year":"2012","journal-title":"J Gastroenterol Hepatol"},{"key":"hep32491-bib-0047-20241017","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1037\/a0031034","article-title":"Mediation analysis allowing for exposure\u2013mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros","volume":"18","year":"2013","journal-title":"Psychol Methods"},{"key":"hep32491-bib-0048-20241017","article-title":"Prevalence of high\u2010risk nonalcoholic steatohepatitis (NASH) in the United States: results from NHANES 2017\u20132018","year":"2021","journal-title":"Clin Gastroenterol Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.32491","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.32491","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32491","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T19:50:02Z","timestamp":1729194602000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32491"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,21]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.32491","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,21]]},"assertion":[{"value":"2021-11-09","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-03-27","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}