Zee R Y L, Cook N R, Cheng S, Erlich H A, Lindpaintner K, Ridker P M
Center for Cardiovascular Disease Prevention, Harvard Medical School, Boston, MA 02215, USA.
J Thromb Haemost. 2006 Feb;4(2):341-8. doi: 10.1111/j.1538-7836.2006.01754.x.
Polymorphisms in candidate genes related to lipid metabolism, thrombosis, hemostasis, cell-matrix adhesion, and inflammation have been suggested clinically useful in risk assessment of cardiovascular disease.
We evaluated a panel of 92 candidate gene polymorphisms, using a multiplex polymerase chain reaction-immobilized probe assay amongst 523 individuals who subsequently developed myocardial infarction (MI), and amongst 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years.
Of the 92 polymorphisms tested, three that we previously reported on were associated with risk of MI, [pro12ala in the peroxisome proliferator activated-receptor gamma gene (odds ratio, OR = 0.75, P = 0.02); thr164ile in the beta-2 adrenergic receptor gene (OR = 0.14, P = 0.007); and ala23thr polymorphism in the eotaxin gene (OR = 1.87, P = 0.01)]. However, when adjusted for the other 89 polymorphisms evaluated, these findings were no longer statistically significant. Further, in contrast to reports from other investigators, we found little evidence for association of a C677T polymorphism in the 5,10-methylenetetrahydrofolate reductase gene, the angiotensin-I-converting enzyme 1 insertion/deletion polymorphism, a 4G/5G polymorphism in the serine/cysteine proteinase inhibitor-clade E-member 1 gene, the factor V Leiden mutation, the G20210A factor II mutation, a -455G>A polymorphism in the beta-fibrinogen gene, the cys112arg/arg158cys apolipoprotein E gene polymorphism, a gly460trp polymorphism in the alpha-adducin gene, and a -629C>A polymorphism in the cholesteryl ester transfer protein gene with risk of MI.
After correction for multiple comparisons, the addition of genetic information observed in the present study had little impact on risk prediction models for MI. The present investigation highlights the importance of replication and validation of findings from genetic association studies.
与脂质代谢、血栓形成、止血、细胞-基质黏附及炎症相关的候选基因多态性在心血管疾病风险评估中已显示出临床应用价值。
我们采用多重聚合酶链反应-固定探针分析法，对523例随后发生心肌梗死（MI）的个体以及2092例在平均13.2年的随访期内未发生心血管疾病报告的个体，评估了一组92个候选基因多态性。
在检测的92个多态性中，我们之前报道的3个与MI风险相关，[过氧化物酶体增殖物激活受体γ基因中的pro12ala（比值比，OR = 0.75，P = 0.02）；β-2肾上腺素能受体基因中的thr164ile（OR = 0.14，P = 0.007）；以及嗜酸性粒细胞趋化因子基因中的ala23thr多态性（OR = 1.87，P = 0.01）]。然而，在对评估的其他89个多态性进行校正后，这些发现不再具有统计学意义。此外，与其他研究者的报告相反，我们几乎没有发现5,10-亚甲基四氢叶酸还原酶基因中的C677T多态性、血管紧张素-I转换酶1插入/缺失多态性、丝氨酸/半胱氨酸蛋白酶抑制剂-E族成员1基因中的4G/5G多态性、因子V莱顿突变、因子II G20210A突变、β-纤维蛋白原基因中的-455G>A多态性、载脂蛋白E基因的cys112arg/arg158cys多态性、α-内收蛋白基因中的gly460trp多态性以及胆固醇酯转运蛋白基因中的-629C>A多态性与MI风险相关的证据。
在进行多重比较校正后，本研究中观察到的遗传信息添加对MI风险预测模型影响不大。本研究强调了基因关联研究结果重复和验证的重要性。
