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Association of AHSG gene polymorphisms with fetuin-A plasma levels and cardiovascular diseases in the EPIC-Potsdam study

Item Type:Article
Title:Association of AHSG gene polymorphisms with fetuin-A plasma levels and cardiovascular diseases in the EPIC-Potsdam study
Creators Name:Fisher, E. and Stefan, N. and Saar, K. and Drogan, D. and Schulze, M.B. and Fritsche, A. and Joost, H.G. and Haering, H.U. and Huebner, N. and Boeing, H. and Weikert, C.
Abstract: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 microg/mL increase per C-allele, P= 2 x 10(-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.
Keywords:Fetuin-A, {alpha}2-HS Glycoprotein, Tagging Single-Nucleotide Polymorphism, Myocardial Infarction, Ischemic Stroke, Prospective Cohort Study, Mendelian Randomization
Source:Circulation Cardiovascular Genetics
Publisher:Lippincott Williams & Wilkins
Page Range:607-613
Date:December 2009
Official Publication:https://doi.org/10.1161/CIRCGENETICS.109.870410
PubMed:View item in PubMed

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