Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response:: a prospective cohort study
Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response:: a prospective cohort study
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DOI：
10.1016/s1474-4422(06)70500-2
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发表时间：
2006-08-01
期刊：
影响因子：
48
通讯作者：
Johnson, Michael R.
中科院分区：
文献类型：
--
作者：
Leschziner, Guy;Jorgensen, Andrea L.;Johnson, Michael R.
在三项回顾性病例对照研究中，ABCB 1 3435 C-->T单核苷酸多态性（SNP）或含有3435 C--> T的三SNP单倍型与癫痫的多药耐药有关，但另外三项研究未能复制这种关联。我们的目的是确定ABCB 1基因对癫痫药物反应的影响，使用一个独特的前瞻性测量癫痫发作和药物反应outcomes.Methods的癫痫患者的大队列ABCB 1 3435 C-->T多态性和三个SNP单倍型，加上一套全面的标签SNP跨越ABCB 1和相邻ABCB 4，对503例癫痫患者进行基因分型，前瞻性测量癫痫发作和药物反应结果。分析了临床、人口统计学和遗传学数据。治疗结果以12个月缓解时间、首次癫痫发作时间和因癫痫控制不佳或副作用而停药的时间来衡量。对所有患者随机选择的全基因组HapMap SNP（n=129）进行基因分型，以进行基因组控制。发现治疗前的癫痫发作次数是预测开始抗癫痫药物治疗后癫痫发作结果的主要特征，通过至首次癫痫发作的时间来衡量（风险比1.34，95%CI 1.21-1.49，pT多态性，三SNP单倍型，或任何全基因标签SNP与开始药物治疗后第一次癫痫发作的时间、12个月缓解的时间或由于不可接受的副作用或缺乏癫痫发作控制而停药的时间的关系。
Background The ABCB1 3435C-->T single-nucleotide polymorphism (SNP) or a three-SNP haplotype containing 3435C --> T has been implicated in multidrug resistance in epilepsy in three retrospective case-control studies, but a further three have failed to replicate the association. We aimed to determine the effect of the ABCB1 gene on epilepsy drug response, using a unique large cohort of epilepsy patients with prospectively measured seizure and drug response outcomes.Methods The ABCB1 3435C-->T polymorphism and three-SNP haplotype, plus a comprehensive set of tag SNPs across ABCB1 and adjacent ABCB4, were genotyped in a cohort of 503 epilepsy patients with prospectively measured seizure and drug response outcomes. Clinical, demographic, and genetic data were analysed. Treatment outcome was measured in terms of time to 12-month remission, time to first seizure, and time to drug withdrawal due to inadequate seizure control or side-effects. Randomly selected genome-wide HapMap SNPs (n=129) were genotyped in all patients for genomic control.Findings Number of seizures before treatment was the dominant feature predicting seizure outcome after starting antiepileptic drug therapy, measured by both time to first seizure (hazard ratio 1.34, 95% Cl 1.21-1.49, pT polymorphism, the three-SNP haplotype, or any gene-wide tag SNP with time to first seizure after starting drug therapy, time to 12-month remission, or time to drug withdrawal due to unacceptable side-effects or to lack of seizure control.Interpretation We found no evidence that ABCB1 common variation influences either seizure or drug withdrawal outcomes after initiation of antiepileptic drug therapy.