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

Abstract

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.

Keywords: case–control study; hepatocellular carcinoma; inflammation; proteomics.

FIGURE 1

Descriptive analysis of pre-diagnostic plasma proteins investigated in relation to HCC risk. (A) Pre-diagnostic plasma protein associations with HCC risk in a nested case–control study of 56 incident HCC cases and 56 individually matched controls with no history of HCC. Red labeled dots are the 15 proteins that demonstrated a statistically significant association with HCC (when modeled as continuous variables; false discovery rate-adjusted [FDR] p value <.05 [Wald test]); Blue unlabeled dots are proteins that did not demonstrate a statistically significant association with HCC risk (when modeled as continuous variables; FDR p value >.05). Odds ratios per one sex-specific standard deviation increase in plasma protein level are from conditional logistic regression models stratified on the matching factors (age, sex, race/ethnicity, blood draw year). (B) Distribution of pre-diagnostic plasma levels for the 15 proteins with levels that differed significantly between HCC cases and HCC-free controls. Values are shown on the inverse normalized transformed scale. (C) Pairwise Pearson correlations between pre-diagnostic plasma proteins significantly associated with HCC risk. Red indicates a positive correlation and blue indicates a negative correlation. CCL19, C-C motif chemokine 19; CCL20, C-C motif chemokine 20; CDCP1, CUB domain-containing protein 1; CSF-1, macrophage colony-stimulating factor 1; CXCL10, C-X-C motif chemokine 10; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; IL10, interleukin-10; IL-15RA, interleukin-15 receptor subunit alpha; IL-18, interleukin-18; LIF-R, leukemia inhibitory factor receptor; OPG, osteoprotegerin; PD-L1, programmed cell death 1 ligand 1; SCF, stem cell factor; SLAMF1, signaling lymphocytic activation molecule; TWEAK, tumor necrosis factor (Ligand) superfamily, member 12.

FIGURE 2

Associations between pre-diagnostic plasma protein levels and HCC risk according to years between blood draw and HCC diagnosis dates for the 15 proteins with the most statistically significant associations with HCC risk. (A) Forest plot of the associations between a one sex-specific standard deviation increase in pre-diagnostic protein level and HCC risk stratified by interval from blood draw date to HCC diagnosis date (<10, ≥10 years). Odds ratios and 95% confidence intervals were estimated from conditional logistic model stratified on the matching factors (age, sex, race/ethnicity, and blood draw year). (B) Variability of associations between pre-diagnostic plasma protein levels and HCC risk according to time interval from blood draw date to HCC diagnosis date. In each matched case–control pair, the HCC-free controls share the same time interval with the HCC cases. CCL19, C-C motif chemokine 19; CCL20, C-C motif chemokine 20; CDCP1, CUB domain-containing protein 1; CI, confidence intervals; CSF-1, macrophage colony-stimulating factor 1; CXCL10, C-X-C motif chemokine 10; FDR, false discovery rate; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; IL10, interleukin-10; IL-15RA, interleukin-15 receptor subunit alpha; IL-18, interleukin-18; LIF-R, leukemia inhibitory factor receptor; OPG, osteoprotegerin; OR, odds ratio; PD-L1, programmed cell death 1 ligand 1; SCF, stem cell factor; SLAMF1, signaling lymphocytic activation molecule; TWEAK, tumor necrosis factor (Ligand) superfamily, member 12.