Fisher Eva, Stefan Norbert, Saar Kathrin, Drogan Dagmar, Schulze Matthias B, Fritsche Andreas, Joost Hans-Georg, Häring Hans-Ulrich, Hubner Norbert, Boeing Heiner, Weikert Cornelia
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
Circ Cardiovasc Genet. 2009 Dec;2(6):607-13. doi: 10.1161/CIRCGENETICS.109.870410. Epub 2009 Sep 5.
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.
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).
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.
血液中胎球蛋白-A循环水平升高与心血管疾病风险增加相关。我们研究的目的是通过应用孟德尔随机化方法，前瞻性地研究胎球蛋白-A水平与心肌梗死（MI）及缺血性卒中之间关联的潜在因果性质。
在欧洲癌症与营养前瞻性调查-波茨坦研究中的一个病例队列中，对五个标记单核苷酸多态性（rs2248690、rs2070633、rs2070635、rs4917和rs6787344）进行基因分型，该队列包括214例MI病例、154例缺血性卒中病例以及2152例未发生心血管疾病事件的人。由于哈迪-温伯格失衡，一个单核苷酸多态性（rs6787344）被排除。所有AHSG标记单核苷酸多态性均与胎球蛋白-A血浆水平相关（P<0.0001）。AHSG rs4917 C>T显示出最强的关联，在不考虑潜在混杂因素的情况下解释了21.2%的表型变异（每C等位基因增加35.5μg/mL，P=2×10⁻¹²¹）。此外，rs4917 C等位基因与MI显著相关（调整后的风险率比[RR]为1.34，95%CI为1.05至1.70，P=0.02）。基于这种关联，胎球蛋白-A中1个标准差对应的MI预期RR为1.54，因此与先前观察到的胎球蛋白-A血浆水平与MI风险之间的关联（RR 1.59）惊人地匹配。
这些数据为最近报道的胎球蛋白-A血浆水平与MI风险之间关联的因果性质提供了证据，从而表明胎球蛋白-A参与了心血管疾病的发病机制。
