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In this study, we investigated the epidemiology of NAFLD and the impact of <jats:italic>PNPLA3<\/jats:italic> on prognosis in Japan.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A longitudinal multicentre cohort study, the JAGUAR study, includes 1550 patients with biopsy\u2010proven NAFLD in Japan. We performed genetic testing and evaluated outcomes from this cohort. Liver\u2010related events were defined as hepatocellular carcinoma (HCC) and decompensated liver cirrhosis events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During follow\u2010up (median [range], 7.1 [1.0\u201324.0] years), 80 patients developed HCC, 104 developed liver\u2010related events, and 59 died of any cause. The 5\u2010year rate of liver\u2010related events for each single\u2010nucleotide polymorphism was 0.5% for CC, 3.8% for CG, and 5.8% for GG. Liver\u2010related deaths were the most common (<jats:italic>n<\/jats:italic>\u2009=\u200928); only three deaths were due to cardiovascular disease. Multivariate analysis identified carriage of <jats:italic>PNPLA3<\/jats:italic> CG\/GG (hazard ratio [HR] 16.04, <jats:italic>p<\/jats:italic>\u2009=\u2009.006) and FIB\u20104 index &gt;2.67 (HR 10.70, <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.01) as predictors of liver\u2010related event development. No HCC or liver\u2010related death was found among patients with <jats:italic>PNPLA3<\/jats:italic> CC. There was a significantly increased risk of HCC, liver\u2010related events, and mortality for CG\/GG versus CC, but no difference between the CG and GG genotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In Japanese individuals, the main cause of death from NAFLD is liver\u2010related death. The greater risk of liver\u2010related events incurred by <jats:italic>PNPLA3<\/jats:italic> G allele was shown in Japan. Risk stratification for NAFLD in Japan is best accomplished by integrating <jats:italic>PNPLA3<\/jats:italic> with the FIB\u20104 index.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15678","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T07:40:54Z","timestamp":1689838854000},"page":"2210-2219","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The greater impact of <scp><i>PNPLA3<\/i><\/scp> polymorphism on liver\u2010related events in Japanese non\u2010alcoholic fatty liver disease patients: A multicentre cohort study"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3658-5894","authenticated-orcid":false,"given":"Yuya","family":"Seko","sequence":"first","affiliation":[{"name":"Molecular Gastroenterology and Hepatology, Graduate School of Medical Science Kyoto Prefectural University of Medicine  Kyoto 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Saga University Hospital  Saga Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miwa","family":"Kawanaka","sequence":"additional","affiliation":[{"name":"General Internal Medicine 2 General Medical Center, Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiyu","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Center for Digestive and Liver Diseases Nara City Hospital  Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhide","family":"Mitsumoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Saiseikai Suita Hospital  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Yoneda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Yokohama City University Graduate School of Medicine  Yokohama 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