Pre-diagnostic plasma inflammatory proteins and risk of hepatocellular carcinoma in three population-based cohort studies from the United States and the United Kingdom

Previous studies suggest a role for inflammation in hepatocarcinogenesis. 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–control study in the Nurses' Health Study (NHS) and the Health Professionals Follow-up 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-HCC controls). Inflammatory protein levels were measured in pre-diagnostic plasma using the Olink® Inflammation Panel. We used conditional logistic regression to calculate multivariable odds ratios (ORs) with 95% confidence intervals (CIs) for associations between a 1-standard deviation (SD) increase in biomarker levels and HCC risk, considering a statistically significant threshold of false discovery rate (FDR)-adjusted p <.05. In the NHS/HPFS, among 70 analyzed proteins with call rates >80%, 15 proteins had significant associations with HCC risk (p_FDR <.05). Two proteins (stem cell factor, OR _{per SD} = 0.31, 95% CI = 0.16–0.58; tumor necrosis factor superfamily member 12, OR _{per SD} = 0.51, 95% CI = 0.31–0.85) were inversely associated whereas 13 proteins were positively associated with risk of HCC; positive ORs _{per SD} ranged from 1.73 for interleukin (IL)-10 to 2.35 for C-C motif chemokine-19. 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-linked immunosorbent assay, with ORs ranging from 1.56 for IL-10 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.