Prospective and Mendelian randomization analyses on the association of circulating fatty acid binding protein 4 (FABP-4) and risk of colorectal cancer

Katharina Nimptsch, Krasimira Aleksandrova, Thu Thi Pham, Nikos Papadimitriou, Jürgen Janke, Sofia Christakoudi, Alicia Heath, Anja Olsen, Anne Tjønneland, Matthias B. Schulze, Verena Katzke, Rudolf Kaaks, Bethany van Guelpen, Justin Harbs, Domenico Palli, Alessandra Macciotta, Fabrizio Pasanisi, Sandra Milena Colorado Yohar, Marcela Guevara, Pilar AmianoSara Grioni, Paula Gabriela Jakszyn, Jane C. Figueiredo, N. Jewel Samadder, Christopher I. Li, Victor Moreno, John D. Potter, Robert E. Schoen, Caroline Y. Um, Elisabete Weiderpass, Mazda Jenab, Marc J. Gunter, Tobias Pischon

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Background: Fatty acid binding protein 4 (FABP-4) is a lipid-binding adipokine upregulated in obesity, which may facilitate fatty acid supply for tumor growth and promote insulin resistance and inflammation and may thus play a role in colorectal cancer (CRC) development. We aimed to investigate the association between circulating FABP-4 and CRC and to assess potential causality using a Mendelian randomization (MR) approach. Methods: The association between pre-diagnostic plasma measurements of FABP-4 and CRC risk was investigated in a nested case-control study in 1324 CRC cases and the same number of matched controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A two-sample Mendelian randomization study was conducted based on three genetic variants (1 cis, 2 trans) associated with circulating FABP-4 identified in a published genome-wide association study (discovery n = 20,436) and data from 58,131 CRC cases and 67,347 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Results: In conditional logistic regression models adjusted for potential confounders including body size, the estimated relative risk, RR (95% confidence interval, CI) per one standard deviation, SD (8.9 ng/mL) higher FABP-4 concentration was 1.01 (0.92, 1.12) overall, 0.95 (0.80, 1.13) in men and 1.09 (0.95, 1.25) in women. Genetically determined higher FABP-4 was not associated with colorectal cancer risk (RR per FABP-4 SD was 1.10 (0.95, 1.27) overall, 1.03 (0.84, 1.26) in men and 1.21 (0.98, 1.48) in women). However, in a cis-MR approach, a statistically significant association was observed in women (RR 1.56, 1.09, 2.23) but not overall (RR 1.23, 0.97, 1.57) or in men (0.99, 0.71, 1.37). Conclusions: Taken together, these analyses provide no support for a causal role of circulating FABP-4 in the development of CRC, although the cis-MR provides some evidence for a positive association in women, which may deserve to be investigated further.

Idioma originalInglés
Número de artículo391
PublicaciónBMC Medicine
EstadoPublicada - dic 2023


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