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It remained unclear whether functional vitamin D\u2010related variants modify these associations. During follow\u2010up of 401,551 UK Biobank participants with valid 25(OH)D data, we documented 4404 incident non\u2010alcoholic fatty liver disease (NAFLD), 1989 incident cirrhosis, and 480 incident liver cancer. The binding affinity values of 25(OH)D to vitamin D binding protein (VDBP) were estimated based on combinations of <jats:italic>VDBP<\/jats:italic> variants rs4588 and rs7041. Vitamin D receptor (VDR) activity was calculated by summing the number of related alleles for rs11568820, rs2228570, and rs1544410. Hazard ratio (95% confidence intervals) for serum 25(OH)D of \u226550\u2009nmol\/L (vs. &lt;25\u2009nmol\/L) were 0.70 (0.63\u20130.77) for NAFLD (<jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009=\u20091.37\u2009\u00d7\u200910<jats:sup>\u221214<\/jats:sup>), 0.43 (0.38\u20130.49) for cirrhosis (<jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009=\u20098.66\u2009\u00d7\u200910<jats:sup>\u221229<\/jats:sup>) and 0.65 (0.48\u20130.87) for liver cancer (<jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009=\u2009.010). We observed differential associations of 25(OH)D with hepatic fibrosis and cirrhosis (<jats:italic>p<\/jats:italic><jats:sub>interaction<\/jats:sub>\u2009=\u2009.024), and portal hypertension (<jats:italic>p<\/jats:italic><jats:sub>interaction<\/jats:sub>\u2009=\u2009.019) by VDR activity, with a stronger inverse association among participants with low VDR activity (<jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009=\u20091.28\u2009\u00d7\u200910<jats:sup>\u22129<\/jats:sup> for hepatic fibrosis and cirrhosis and <jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009=\u20091.52\u2009\u00d7\u200910<jats:sup>\u221214<\/jats:sup> for portal hypertension). The association of 25(OH)D with liver cancer differed by <jats:italic>GC<\/jats:italic> isoforms (<jats:italic>p<\/jats:italic><jats:sub>interaction<\/jats:sub>\u2009=\u2009.033), with a stronger inverse association among participants with low affinity isoforms (<jats:italic>p<\/jats:italic><jats:sub>trend<\/jats:sub>\u2009=\u2009.001). Serum 25(OH)D appears to prevent NAFLD, cirrhosis, and liver cancer, especially for participants with low VDR activity\/low affinity <jats:italic>GC<\/jats:italic> isoforms.<\/jats:p>","DOI":"10.1002\/ijc.35522","type":"journal-article","created":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T05:32:40Z","timestamp":1749879160000},"page":"1781-1794","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Serum 25\u2010hydroxyvitamin D, vitamin D\u2010related variants, and risk of chronic liver disease"],"prefix":"10.1002","volume":"157","author":[{"given":"Qian","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College Huazhong University of Science and Technology  Wuhan Hubei 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