Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Atherosclerosis. 2011 Aug;217(2):458-64. doi: 10.1016/j.atherosclerosis.2011.06.023. Epub 2011 Jun 17.
Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p<0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.
遗传变异已被证明会影响他汀类药物的反应性。乌得勒支心血管药物遗传学（UCP）研究的参与者是从与医院出院记录相关的基于人群的药房记录登记处招募的，以研究胆固醇降低途径中涉及的候选基因内的标记 SNP，以改变他汀类药物降低心肌梗死（MI）风险的有效性。从 PHARMO 数据库中选择接受抗高血压药物处方和/或患有高胆固醇血症的患者。我们设计了一个嵌套病例对照研究，其中病例因 MI 住院，对照则没有。通过他们的社区药房与患者联系。本研究仅选择高胆固醇血症参与者。逻辑回归分析用于研究药物遗传学相互作用。心脏和血管健康研究（HVH）用于复制 UCP 的发现。研究人群包括 668 例病例和 1217 例对照。我们选择了 231 个 SNP，其中 27 个基因中的 209 个 SNP 通过质量控制。在 UCP 中，发现 8 个基因中的 10 个 SNP 影响他汀类药物的有效性，其中与 SCARB1 rs4765615 的相互作用最显著。在 UCP 中达到统计学意义（p<0.05）的其他基因包括 PCSK9 中的两个 SNP（rs10888896 和 rs505151（E670G））、ABCG5 中的两个 SNP（rs4245786 和 rs1864815）、LIPC rs16940379、ABCA1 rs4149264、PPARG rs2972164、LRP1 rs715948 和 SOAT1 rs2493121。在 HVH 中可用于复制的总共 5 个 SNP 中，没有一个达到统计学意义。总之，在 UCP 研究中发现 10 个 SNP 可改变他汀类药物降低 MI 风险的有效性。其中 5 个也在 HVH 研究中进行了测试，但没有相互作用达到统计学意义。
