Soluble Receptor for Advanced Glycation End-products (sRAGE) and Colorectal Cancer Risk: A Case-Control Study Nested within a European Prospective Cohort

Elom K Aglago, Sabina Rinaldi, Heinz Freisling, Li Jiao, Veronika Fedirko, Casper G Schalkwijk, Elisabete Weiderpass, Christina C Dahm, Kim Overvad, Anne Kirstine Eriksen, Cecilie Kyrø, Marie-Christine Boutron-Ruault, Joseph A Rothwell, Gianluca Severi, Verena Katzke, Tilman Kühn, Matthias B Schulze, Krasimira Aleksandrova, Giovanna Masala, Vittorio KroghSalvatore Panico, Rosario Tumino, Alessio Naccarati, Bas Bueno-de-Mesquita, Carla H van Gils, Torkjel M Sandanger, Inger T Gram, Guri Skeie, J Ramón Quirós, Paula Jakszyn, Maria-Jose Sánchez, Pilar Amiano, José María Huerta, Eva Ardanaz, Ingegerd Johansson, Sophia Harlid, Aurora Perez-Cornago, Ana-Lucia Mayén, Reynalda Cordova, Marc J Gunter, Paolo Vineis, Amanda J Cross, Elio Riboli, Mazda Jenab

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation.

METHODS: To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively.

RESULTS: Higher sRAGE concentrations were inversely associated with colorectal cancer (ORQ5vs.Q1, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (ORQ5vs.Q1, 1.00; 95% CI, 0.68-1.48; Pheterogeneity for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99).

CONCLUSIONS: Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within ADAM10 gene, pertaining to RAGE shedding, was associated with colorectal cancer risk.

IMPACT: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.

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