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

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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., Stefan, N., Saar, K., Drogan, D., Schulze, M.B., Fritsche, A., Joost, H.G., Haering, H.U., Huebner, N., 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
ISSN:	1942-325X
Publisher:	Lippincott Williams & Wilkins
Volume:	2
Number:	6
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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