Abstract 2200: Plasma Fetuin-a concentration, genetic variation in the AHSG gene and risk of colorectal cancer

Abstract

Abstract Background: Fetuin-a, also referred to as α2-Heremans-Schmid glycoprotein (AHSG) is a liver protein that inhibits insulin actions. High circulating fetuin-a concentrations have been associated with insulin resistance and hyperinsulinemia, which pose risk factors for colorectal cancer. Experimental studies have also shown that fetuin-a mediates the adhesion of tumor cells, an important step in tumor growth through which fetuin-a could influence colorectal cancer risk independent of the insulin axis. With this study, we aimed to investigate the prospective association between circulating fetuin-a and risk of colorectal cancer. In addition, we examined potential causality of observed associations by using single nucleotide polymorphisms (SNPs) in the AHSG gene as relatively unbiased proxies for fetuin-a levels in a Mendelian Randomization approach. Methods: Fetuin-a levels were measured in plasma samples from a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) comprising 1367 cases and 1367 matched controls (matching variables included age, sex, study center and fasting status). In a subset of 456 case-control pairs, five tagging SNPs in the AHSG gene (rs2248690, rs2070633, rs2070635, rs4917 and rs6787344) were genotyped. The association between circulating fetuin-a and risk of colorectal cancer was investigated using conditional logistic regression models (controlled for matching factors and multivariable adjusted for education, physical activity, smoking, alcohol consumption, dietary factors and body fatness) estimating incidence rate ratios (RRs) and 95% confidence intervals (CI). The association between genetically raised fetuin-a and risk of colorectal cancer was estimated by instrumental variable analysis using two-stage least squares regression. Results: Higher fetuin-a concentrations were associated with a moderately higher risk of colorectal cancer: The estimated RRs (95% CI) per 40 µg/mL higher fetuin-a were 1.11 (1.01, 1.22) overall, 1.18 (1.03, 1.37) in men, 1.05 (0.92, 1.21) in women, 1.11 (0.99, 1.25) for colon cancer and 1.10 (0.92, 1.30) for rectal cancer. In the subset of participants with available data on both plasma fetuin-a and AHSG SNPs, the AHSG allele score explained 21% of the inter-individual variation in plasma fetuin-a. When using the AHSG-score as instrumental variable in a Mendelian randomization approach, there was no association between genetically determined fetuin-a and risk of colorectal cancer: RR (95% CI) per 40 µg/mL genetically determined higher fetuin-a was 0.98 (0.73, 1.33) overall, 1.04 (0.68, 1.60) in men and 0.93 (0.62, 1.42) in women. Conclusion: This is the first prospective study relating circulating fetuin-a to risk of colorectal cancer. Our findings suggest that high fetuin-a concentrations are associated with a moderately higher risk of colorectal cancer, but that fetuin-a is probably not a causal factor. Citation Format: Katharina Nimptsch, Krasimira Aleksandrova, Heiner Boeing, Jürgen Janke, Young-Ae Lee, Mazda Jenab, Bas Bueno-De-Mesquita, Konstantinos K. Tsilidis, Elisabete Weiderpass Vainio, Eugène HJM Jansen, Timothy J. Key, Antonia Trichopoulou, Kim Overvad, Elio Riboli, Tobias Pischon, European Prospective Investigation into Cancer andNutrition (EPIC). Plasma Fetuin-a concentration, genetic variation in the AHSG gene and risk of colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2200. doi:10.1158/1538-7445.AM2014-2200