Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 2, Issue 6, Pages 607-U192Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.109.870410
Keywords
fetuin-A; alpha(2)-HS glycoprotein; tagging single-nucleotide polymorphism; myocardial infarction; ischemic stroke; prospective cohort study; Mendelian randomization
Funding
- Federal Ministry of Science [01 EA 9401]
- European Union [SOC 95201408 05F02]
- German Cancer Aid [70-2488-Ha I]
- European Community [SOC 98200769 05F02]
- German Research Foundation [STE 1096/1-1]
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Background-Elevated circulating levels of fetuin-A in blood have been associated with increased risk of cardiovascular disease. The goal of our study was to prospectively investigate the potential causal nature of the association between fetuin-A levels and myocardial infarction (MI) and ischemic stroke by applying a Mendelian randomization approach. 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 alpha(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 mu g/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. (Circ Cardiovasc Genet. 2009;2:607-613.)
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