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However, no study has comprehensively evaluated associations between circulating inflammatory proteins and risk of hepatocellular carcinoma (HCC) among the general population. We conducted a nested case\u2013control study in the Nurses' Health Study (NHS) and the Health Professionals Follow\u2010up Study (HPFS) with 56 pairs of incident HCC cases and controls. External validation was performed in the UK Biobank (34 HCC cases and 48,471 non\u2010HCC controls). Inflammatory protein levels were measured in pre\u2010diagnostic plasma using the Olink\u00ae Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1\u2010standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)\u2010adjusted <jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05. In the NHS\/HPFS, among 70 analyzed proteins with call rates &gt;80%, 15 proteins had significant associations with HCC risk (<jats:italic>p<\/jats:italic><jats:sub><jats:italic>FDR<\/jats:italic><\/jats:sub>\u2009&lt;\u2009.05). Two proteins (stem cell factor, OR <jats:sub>per SD<\/jats:sub>\u2009=\u20090.31, 95% CI\u2009=\u20090.16\u20130.58; tumor necrosis factor superfamily member 12, OR <jats:sub>per SD<\/jats:sub>\u2009=\u20090.51, 95% CI\u2009=\u20090.31\u20130.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs <jats:sub>per SD<\/jats:sub> ranged from 1.73 for interleukin (IL)\u201010 to 2.35 for C\u2010C motif chemokine\u201019. A total of 11 proteins were further replicated in the UK Biobank. Seven of the eight selected positively associated proteins also showed positive associations with HCC risk by enzyme\u2010linked immunosorbent assay, with ORs ranging from 1.56 for IL\u201010 to 2.72 for hepatocyte growth factor. More studies are warranted to further investigate the roles of these observed inflammatory proteins in HCC etiology, early detection, risk stratification, and disease treatment.<\/jats:p>","DOI":"10.1002\/ijc.35054","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T19:16:23Z","timestamp":1718133383000},"page":"1593-1603","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pre\u2010diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population\u2010based cohort studies from the <scp>United States<\/scp> and the <scp>United Kingdom<\/scp>"],"prefix":"10.1002","volume":"155","author":[{"given":"Longgang","family":"Zhao","sequence":"first","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brenda M.","family":"Birmann","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher J.","family":"Danford","sequence":"additional","affiliation":[{"name":"Transplant Services Intermountain Medical Center  Murray Utah USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracey G.","family":"Simon","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Clinical and Translational Epidemiology Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew T.","family":"Chan","sequence":"additional","affiliation":[{"name":"Channing Division of Network Medicine, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"},{"name":"Division of Gastroenterology Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Clinical and Translational Epidemiology Unit Massachusetts General Hospital, Harvard Medical School  Boston Massachusetts USA"},{"name":"Broad Institute of Massachusetts Institute of Technology and Harvard  Boston Massachusetts USA"},{"name":"Department of Immunology and Infectious Diseases Harvard T.H. Chan School of Public Health  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward L.","family":"Giovannucci","sequence":"additional","affiliation":[{"name":"Department of Nutrition Harvard T.H. Chan School of Public Health  Boston Massachusetts USA"},{"name":"Department of Epidemiology Harvard T.H. Chan School of Public Health  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Ngo","sequence":"additional","affiliation":[{"name":"Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School  Boston Massachusetts USA"},{"name":"Department of Biostatistics Harvard T.H. 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