Fiegenbaum Marilu, da Silveira Fabiano R, Van der Sand Cézar R, Van der Sand Luiz Carlos, Ferreira Maria E W, Pires Renan C, Hutz Mara H
Departamento de Genética, Centro de Diagnóstico Cardiológico, Universidade Federal do Rio Grande do Sul, 91501-970 Porto Alegre, RS, Brazil.
Clin Pharmacol Ther. 2005 Nov;78(5):551-8. doi: 10.1016/j.clpt.2005.08.003. Epub 2005 Sep 26.
Our objective was to investigate the interactions between common polymorphisms in ABCB1, CYP3A4, and CYP3A5 genes and the lipid-lowering efficacy and safety of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin.
One hundred sixteen hypercholesterolemic patients were prospectively screened by physical examination, medical history, and clinical laboratory evaluation and were included in this study. Subjects entering the study were treated with 20 mg/d simvastatin. Plasma lipid and lipoprotein levels were measured before treatment, after 2 months of treatment, and after 6 months of treatment. Ninety-nine patients completed the 6-month follow-up and were included in the association analysis for treatment efficacy. Seventeen subjects who had adverse drug reactions (ADRs) to simvastatin (ADR group) could not complete the 6-month follow-up and were included in the association analyses for safety. Myalgia was observed in 15 of 17 subjects and was the only ADR included in the association analyses, but other common ADRs were also observed. Myalgia was defined as proximal or diffuse muscle pain, tenderness, or weakness, or both pain and weakness, with normal or slightly increased serum creatine phosphokinase levels. ABCB1 (1236C>T, 2677G>A/T, and 3435C>T), CYP3A4 (-392A>G), and CYP3A5 (6986A>G) allele variants were determined by polymerase chain reaction and restriction mapping.
After adjustment for covariates, carriers of the ABCB1 1236T variant allele had a greater reduction in total cholesterol and low-density lipoprotein cholesterol with simvastatin treatment, as compared with homozygotes with the wild-type allele (-29.0% [95% confidence interval (CI), -25.9 to -32.5] versus -24.2% [95% CI, -19.0 to -29.3] [P = .042] and -39.6% [95% CI, -35.8 to -44.0] versus -33.8% [95% CI, -27.4 to -40.2] [P = .042], respectively). Similar results were observed for the 2677G>A/T polymorphism and haplotype data. The 1236T, 2677non-G, and 3435T alleles were less frequent in ADR cases than in the non-ADR group (P < .05 for all single-nucleotide polymorphisms). Haplotype analyses also demonstrated a reduction of the T-non-G-T haplotype frequency (20%) in patients in whom myalgia developed during simvastatin treatment, as compared with the non-ADR group (41.4%) (P = .03). No significant associations were observed between the CYP3A4 -392A>G and CYP3A5*3 allele variants and the efficacy or tolerability of simvastatin.
Our data suggest an association of ABCB1 gene polymorphisms and the efficacy and safety of simvastatin.
我们的目的是研究ABCB1、CYP3A4和CYP3A5基因常见多态性与3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂辛伐他汀的降脂疗效及安全性之间的相互作用。
通过体格检查、病史和临床实验室评估对116例高胆固醇血症患者进行前瞻性筛查，并纳入本研究。进入研究的受试者接受20mg/d辛伐他汀治疗。在治疗前、治疗2个月后和治疗6个月后测量血脂和脂蛋白水平。99例患者完成了6个月的随访，并纳入治疗疗效的关联分析。17例对辛伐他汀有药物不良反应（ADR）的受试者（ADR组）未能完成6个月的随访，并纳入安全性关联分析。17例受试者中有15例出现肌痛，这是关联分析中唯一纳入的ADR，但也观察到了其他常见ADR。肌痛定义为近端或弥漫性肌肉疼痛、压痛或无力，或疼痛与无力同时存在，血清肌酸磷酸激酶水平正常或略有升高。通过聚合酶链反应和限制性图谱分析确定ABCB1（1236C>T、2677G>A/T和3435C>T）、CYP3A4（-392A>G）和CYP3A5（6986A>G）等位基因变异。
校正协变量后，与野生型等位基因纯合子相比，ABCB1 1236T变异等位基因携带者接受辛伐他汀治疗后总胆固醇和低密度脂蛋白胆固醇降低幅度更大（分别为-29.0%[95%置信区间（CI），-25.9至-32.5]对-24.2%[95%CI，-19.0至-29.3][P = 0.042]和-39.6%[95%CI，-35.8至-44.0]对-33.8%[95%CI，-27.4至-40.2][P = 0.042]）。对于2677G>A/T多态性和单倍型数据也观察到了类似结果。ADR病例中1236T、2677非G和3435T等位基因的频率低于非ADR组（所有单核苷酸多态性的P < 0.05）。单倍型分析还表明，与非ADR组（41.4%）相比，辛伐他汀治疗期间出现肌痛的患者中T-非G-T单倍型频率降低（20%）（P = 0.03）。未观察到CYP3A4 -392A>G和CYP3A5*3等位基因变异与辛伐他汀的疗效或耐受性之间存在显著关联。
我们的数据表明ABCB1基因多态性与辛伐他汀的疗效和安全性相关。
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