Published Online
on September 5, 2009

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Original Article

Association of AHSG Gene Polymorphisms with Fetuin-A Plasma Levels and Cardiovascular Diseases in the EPIC-Potsdam Study

Eva Fisher^1,6; Norbert Stefan²; Kathrin Saar³; Dagmar Drogan¹; Matthias B. Schulze⁴; Andreas Fritsche²; Hans-Georg Joost¹; Hans-Ulrich Häring²; Norbert Huebner³; Heiner Boeing¹ and Cornelia Weikert⁵

¹ German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany;
² University of Tübingen, Tübingen, Germany;
³ Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany;
⁴ Technical University, Munich, Germany;
⁵ German Inst of Human Nutri Potsdam-Rehbrücke & Charité Univ Medicine Berlin, Germany

http://www.dife.de

^* Corresponding author; email: fisher{at}dife.de

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 (IS) applying a Mendelian randomization approach.

Methods and Results—Five tagging single nucleotide polymorphisms (tagSNPs) (rs2248690, rs2070633, rs2070635, rs4917, rs6787344) capturing the common genetic variation of the fetuin-A coding gene alpha2- Heremans-Schmid glycoprotein (AHSG) were genotyped in a case-cohort comprising 214 MI cases, 154 IS cases and 2,152 persons who remained free of cardiovascular disease events of the EPIC-Potsdam study. One SNP (rs6787344) was discarded due to Hardy-Weinberg disequilibrium. All AHSG tagSNPs were associated with fetuin-A plasma levels (P-values<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 1.05-1.70, P=0.02). Based on this association, the expected RR for MI corresponding to 1 standard deviation 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—The present 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.

Key Words: cerebral ischemia • genetics • myocardial infarction • fetuin-A • alpha2-HS glycoprotein • tagging single nucleotide polymorphism • ischemic stroke • prospective cohort study