Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer

Katharina Nimptsch, Krasimira Aleksandrova, Heiner Boeing, Jürgen Janke, Young Ae Lee, Mazda Jenab, So Yeon Kong, Konstantinos K. Tsilidis, Elisabete Weiderpass, H. Bas Bueno-De-Mesquita, Peter D. Siersema, Eugène H J M Jansen, Antonia Trichopoulou, Anne Tjønneland, Anja Olsen, Chunsen Wu, Kim Overvad, Marie Christine Boutron-Ruault, Antoine Racine, Heinz FreislingVerena Katzke, Rudolf Kaaks, Pagona Lagiou, Dimitrios Trichopoulos, Gianluca Severi, Alessio Naccarati, Amalia Mattiello, Domenico Palli, Sara Grioni, Rosario Tumino, Petra H. Peeters, Ingrid Ljuslinder, Hanna Nyström, Jenny Brändstedt, María José Sánchez, Aurelio Barricarte Gurrea, Catalina Bonet Bonet, María Dolores Chirlaque, Miren Dorronsoro, José Ramõn Quirõs, Ruth C. Travis, Kay Tee Khaw, Nick Wareham, Elio Riboli, Marc J. Gunter, Tobias Pischon

Research output: Contribution to journalArticlepeer-review


Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 μg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 μg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development. What's new? Fetuin-A is a liver protein associated with insulin resistance, but with no defined role yet in colorectal cancer. In this prospective study, the authors uncover a modest linear association between fetuin-A levels and higher risk of colorectal cancer, but this was only observed in male participants. In addition, no association was observed between fetuin-A variants and colorectal cancer risk in a Mendelian randomization analysis, arguing against a direct role of fetuin-A in colorectal carcinogenesis.

Original languageEnglish
Pages (from-to)911-920
Number of pages10
JournalInternational Journal of Cancer
Issue number4
Publication statusPublished - Aug 15 2015


  • AHSG
  • colorectal cancer
  • fetuin-A

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)


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