Pharmacovigilance Unit, Agency for Medicinal Products & Medical Devices, Ksaverska Cesta 4, 10000 Zagreb, Croatia.
Pharmacogenomics. 2013 Sep;14(12):1419-31. doi: 10.2217/pgs.13.135.
To investigate whether an association exists between fluvastatin-induced adverse drug reactions (ADRs) and polymorphisms in genes encoding the metabolizing enzyme CYP2C9 and the drug transporter ABCG2 in renal transplant recipients (RTRs).
MATERIALS & METHODS: Fifty-two RTRs that experienced fluvastatin ADRs and 52 controls matched for age, gender, dose of fluvastatin and immunosuppressive use were enrolled in the study. Genotyping for CYP2C9*2, *3 and ABCG2 421C>A variants was performed by real-time PCR.
CYP2C9 homozygous and heterozygous mutant allele (*2 or *3) carriers had 2.5-times greater odds of developing adverse effects (χ² = 4.370; degrees of freedom = 1; p = 0.037; φ = 0.21, odds ratio [OR]: 2.44; 95% CI: 1.05-5.71). Patients who were the carriers of at least one mutant CYP2C9 allele (*2 or *3) and who were receiving CYP2C9 inhibitors, had more than six-times greater odds of having adverse effects than those without the inhibitor included in their therapy (p = 0.027; OR: 6.59; 95% CI: 1.24-35.08). Patients with ABCG2 421CA or AA (taken together) had almost four-times greater odds of developing adverse effects than those with ABCG2 421CC genotype (χ² = 6.190; degrees of freedom = 1; p = 0.013; φ = 0.24, OR: 3.81; 95% CI: 1.27-11.45). Patients with A allele had 2.75-times (95% CI: 1.02-7.40) greater odds of developing adverse effects than those with C allele.
Our preliminary data demonstrate an association between fluvastatin-induced ADRs in RTRs and genetic variants in the CYP2C9 and ABCG2 genes.
研究氟伐他汀诱导的药物不良反应（ADR）与肾移植受者（RTR）中编码代谢酶 CYP2C9 和药物转运蛋白 ABCG2 的基因多态性之间是否存在关联。
本研究纳入了 52 例经历氟伐他汀 ADR 的 RTR 患者和 52 例年龄、性别、氟伐他汀剂量和免疫抑制药物使用相匹配的对照患者。通过实时 PCR 检测 CYP2C9*2、*3 和 ABCG2 421C>A 变体的基因分型。
CYP2C9 纯合和杂合突变等位基因（*2 或 *3）携带者发生不良反应的可能性增加 2.5 倍（χ²=4.370；自由度=1；p=0.037；φ=0.21，优势比[OR]：2.44；95%置信区间：1.05-5.71）。至少携带一个突变 CYP2C9 等位基因（*2 或 *3）且正在接受 CYP2C9 抑制剂治疗的患者发生不良反应的可能性比未接受包括抑制剂在内的治疗的患者高 6 倍以上（p=0.027；OR：6.59；95%置信区间：1.24-35.08）。ABCG2 421CA 或 AA（合并）的患者发生不良反应的可能性几乎是 ABCG2 421CC 基因型患者的 4 倍（χ²=6.190；自由度=1；p=0.013；φ=0.24，OR：3.81；95%置信区间：1.27-11.45）。携带 A 等位基因的患者发生不良反应的可能性比携带 C 等位基因的患者高 2.75 倍（95%置信区间：1.02-7.40）。
我们的初步数据表明，RTR 中氟伐他汀诱导的 ADR 与 CYP2C9 和 ABCG2 基因的遗传变异有关。
