Methods and Results— Five tagging single-nucleotide polymorphisms (rs2248690, rs2070633, rs2070635, rs4917, and rs6787344) capturing the common genetic variation of the fetuin-A coding gene ₂-Heremans-Schmid glycoprotein (AHSG) were genotyped in a case-cohort comprising 214 MI cases, 154 ischemic stroke cases, and 2152 persons who remained free of cardiovascular disease events in the European Prospective Investigation into Cancer and Nutrition-Potsdam study. One single-nucleotide polymorphism (rs6787344) was discarded because of Hardy-Weinberg disequilibrium. All AHSG tagging single-nucleotide polymorphisms were associated with fetuin-A plasma levels (P<0.0001). AHSG rs4917 C>T showed the strongest association, explaining 21.2% of the phenotypic variance independent of potential confounding factors (+35.5 µg/mL increase per C-allele, P=2x10^–121). Furthermore, the rs4917 C-allele showed a significant association with MI (adjusted hazard rate ratio [RR] 1.34, 95% CI 1.05 to 1.70, P=0.02). Based on this association, the expected RR for MI corresponding to 1 SD in fetuin-A was 1.54 and, thus, strikingly matches the previously observed association between fetuin-A plasma levels and MI risk (RR 1.59).

Conclusions— These data provide evidence for the causal nature of the recently reported association between fetuin-A plasma levels and MI risk, thereby suggesting an involvement of fetuin-A in the pathogenesis of cardiovascular disease.