Fetuin-A, also referred to as alpha 2-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 mg/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 mg/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
