Human fatty acid binding protein-4 (FABP-4), a protein elevated in obesity that promotes colon cancer cell invasiveness and metastasis, may be associated with higher mortality in individuals with colorectal cancer (CRC) and may serve as a mediator of the obesity-mortality association in these individuals.
We used a causal diagram to inform covariate selection and applied Cox proportional hazards models to estimate hazard ratios (HRs) for CRC-specific, non-CRC-specific, and all-cause mortality by FABP-4 levels measured in baseline blood samples from 1371 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. Competing risk analyses were adapted for CRC and non-CRC deaths. Mediation analyses were conducted to estimate total effects (TEs), direct effects (DEs), and mediation proportions (MPs) by FABP-4 of pre-diagnostic body mass index (BMI) on mortality.

In the fully adjusted model including BMI, higher circulating FABP-4 concentrations were associated with higher CRC mortality (HRQ4vsQ1= 1.49; 95%CI: 1.11, 2.00) and all-cause mortality (HRQ4vsQ1= 1.49; 95%CI: 1.15, 1.93), but not statistically associated with non-CRC mortality (HRQ4vsQ1= 1.51; 95%CI: 0.82, 2.76). The TE and DE per 5 kg/m2 of BMI on all-cause mortality were 1.21; 95%CI: 1.10, 1.34, and 1.13; 95%CI: 1.02, 1.26, respectively, with a MP of 34.5% (p=0.002) by FABP-4. For CRC-specific and non-CRC-specific mortality, MPs by FABP-4 were 33.7% (p=0.03), and 36.1% (p=0.02), respectively.
In conclusion, higher concentrations of FABP-4 were associated with higher CRC-specific and all-cause mortality in individuals with CRC. FABP-4 was a significant partial mediator of the adiposity-mortality relationship in individuals with CRC.