Artikel
Circulating fatty acid binding protein 4 (FABP-4) concentrations and mortality after CRC diagnosis in the European Prospective Investigation into Cancer and Nutrition (EPIC): A survival and a mediation analysis
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Autoren
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Thu Thi Pham
- Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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Katharina Nimptsch
- Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Krasimira Aleksandrova
- Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology — BIPS, Bremen, Germany; Faculty of Human and Health Sciences, University of Bremen, Bremen, Germany
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Mazda Jenab
- Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), World Health Organization, Lyon, France
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Veronika Fedirko
- Department of Epidemiology, University of Texas M. D. Anderson Cancer Center, Houston, United States; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, United States
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Tobias Pischon
- Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany; Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Biobank Technology Platform, Berlin, Germany; Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Core Facility Biobank, Berlin, Germany
| Veröffentlicht: | 6. September 2024 |
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Gliederung
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Introduction: Obesity is associated with higher mortality in individuals with colorectal cancer (CRC); yet, the underlying pathways are unclear. Human fatty acid binding protein-4 (FABP-4), also known as adipocyte protein 2 (aP2), is a 132 amino acid protein that is elevated in obese individuals and involved in insulin resistance, lipid metabolism, inflammation, and angiogenesis. Thus, FABP-4 may qualify as a potential biomarker linking adiposity and mortality in individuals with CRC. We investigated the association of prediagnostic FABP-4 concentrations with mortality in individuals diagnosed with CRC and explored to what extent FABP-4 may mediate the association of obesity with mortality in these persons.
Methods: We estimated hazard ratios (HRs) of CRC-specific mortality, non-CRC-specific mortality, and all-cause mortality by FABP-4 levels measured in baseline blood samples among 1371 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We used Cox-proportional hazards models with time from CRC diagnosis to death or censoring as the underlying time variable, and stratified by country and sex. Competing risk analyses were performed for CRC death and non-CRC death. Subgroup analyses were carried out by sex, tumor site and stage, body mass index (BMI), time to CRC diagnosis, and follow-up time. In the counterfactual-based mediation analysis, we estimated the total effect (TE) of BMI on mortality and the direct effects (DE), which is the effect of obesity on mortality not mediated by FABP-4. We estimated the extent to which FABP-4 mediates the relationship between BMI and mortality as 1- HRDE/ HRTE.
Results: After multivariable adjustment taking into account established risk factors for CRC including BMI and waist circumference residuals higher circulating FABP-4 concentrations were associated with higher all-cause mortality (quartile 4 (Q4) versus quartile 1 (Q1), HR=1.51; 95%CI 1.15, 1.98; p trend=0.02; per SD HR=1.10; 95%CI 1.01, 1.20; p=0.02). The association was somewhat stronger for non-CRC mortality (Q4 vs Q1, HR=1.81; 95%CI 0.97, 3.38; p trend=0.14; per SD HR=1.22; 95%CI 1.03, 1.44, p=0.02) than for CRC mortality (Q4 vs Q1, HR=1.48; 95%CI 1.09, 2.01; p trend=0.03; per SD HR=1.08; 95%CI 0.98, 1.19, p=0.13). Subgroup analyses showed stronger associations in men, in individuals with colon cancer, and in those with BMI<25, although formal tests for interaction were significant only for tumor site, with significant associations for colon but not for rectal cancer (p interaction<0.05). The TE and DE per 5kg/m2 of BMI on CRC-specific mortality were, HRTE; 1.16, 95%CI (1.04, 1.31), HRDE; 1.10, 95%CI (0.96, 1.25), corresponding to a proportion of 39.2%; 95%CI (6.9%, 84.9%), which was mediated by per 1 SD of FABP-4. The associations of BMI with non-CRC-specific and all-cause mortality were mediated by FABP-4 by 39.5%; 95%CI (11.1%, 77.3%), and 39.3%; 95%CI (13.3%, 73.2%), respectively.
Conclusions: Higher concentrations of FABP-4 were associated with all-cause mortality in individuals with CRC, with a stronger association observed for non-CRC compared to CRC mortality. FABP-4 was a significant partial mediator of the adiposity-mortality relationship in individuals with CRC, while the potential mediating role of other biomarkers associated with inflammation and hyperinsulinemia warrants further research.
The authors declare that they have no competing interests.
The authors declare that an ethics committee vote is not required.
