School of Pharmacy, Department of Pharmaceutical Sciences, University of Puerto Rico, San Juan, Puerto Rico.
Ann Pharmacother. 2012 Feb;46(2):208-18. doi: 10.1345/aph.1Q190. Epub 2012 Jan 24.
The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients.
To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.
A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.
Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.
This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.
CYP2C9 和 VKORC1 多态性对华法林剂量的影响已在白种人、亚洲人和非裔美国人中进行了研究，但在波多黎各西班牙裔患者中尚未进行研究。
通过使用已发表的算法，检测基因型、国际标准化比值（INR）测量值与华法林剂量之间的关联，并评估这些多态性对华法林剂量的影响。
对 106 例波多黎各患者进行了回顾性华法林药物遗传学关联研究。通过 HILOmet PhyzioType 测定法对患者的 CYP2C9 和 VKORC1 基因座中的 12 个变体进行 DNA 检测。从病历中回顾性收集人口统计学和临床非遗传数据。确定等位基因和基因型频率，并检验 Hardy-Weinberg 平衡（HWE）。
69%的患者在 CYP2C9 或 VKORC1 基因中至少携带一种多态性。双、三、四重携带者分别占 22%、5%和 1%。未发现明显偏离 HWE。在具有特定 CYP2C9 基因型的患者中，华法林剂量需求从 GG 到 AA 单倍型降低；而在每个 VKORC1 单倍型中，随着 CYP2C9 变体数量的增加，剂量减少。这些失活等位基因的存在与 INR 测量值超出范围的情况更多相关（OR=1.38），但在启动阶段 INR>4 并不显著。基于已发表的药物遗传学算法的分析预测携带者的剂量减少高达 4.9mg/天，并为高度敏感患者的极端亚组提供了更好的剂量预测，但也表明需要通过开发针对波多黎各患者的定制模型来提高可预测性。
本研究为在波多黎各人中进行支持纳入相关基因组信息的前瞻性药物遗传学试验奠定了重要基础，以检测将相关基因组信息纳入定制 DNA 指导的华法林剂量算法的益处。
