Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration
Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration
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DOI：
10.1097/fpc.0b013e3282f70458
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发表时间：
2008-04-01
影响因子：
2.6
通讯作者：
Stricker, Bruno H. Ch.
中科院分区：
文献类型：
--
作者：
Aarnoudse, Albert-Jan L. H. J.;Dieleman, Jeanne P.;Stricker, Bruno H. Ch.
背景与目的地高辛（Digoxin）是ATP结合盒1311（ABCB 1/MDR 1）的底物。然而，ABCB 1多态性和地高辛动力学之间的关联的研究结果仍然是矛盾的。几乎所有研究都是小型研究，仅涉及单次给药动力学。本研究的目的是建立ABCB 1基因型对地高辛血药浓度的影响在一个大的队列中的慢性地高辛用户在一般荷兰欧洲population.Methods地高辛用户被确定在鹿特丹研究，一个前瞻性的人群为基础的队列研究，年龄在55岁及以上的个人。地高辛的血液水平是从地区医院和实验室收集的。使用Taqman分析法对外周血DNA上的ABCB 1单核苷酸多态性（SNP）1236 C-> T、2677 G-> T/A和3435 C-> T进行评估。我们研究了ABCB 1基因型和单倍型之间的关联，地高辛血液水平调整潜在的confers.Results线性回归模型地高辛血清水平和DNA可用于195名参与者（56.4%的妇女，平均年龄79.4岁）。所有三种ABCB 1变异体均与血清地高辛浓度显著相关（每增加一个T等位基因0.18-0.21 μ g/l）。对于1236-2677-3435 TTT单倍型等位基因，这种关联甚至更强[0.26 μ g/l（95%CI 0.14-0.38）]，但其他单倍型不存在（CGC等位基因被认为是指涉的），这表明在因果单倍型中SNP的相互作用，而不是单个SNP的作用。在一般人群中，2677 G-> T和3435 C-> T变异体和相关TTT单倍型与欧洲老年地高辛使用者队列中较高的地高辛血清浓度相关。药理遗传学和基因组学18：299-305（c）2008年沃尔特斯·克鲁沃健康垂直栏Lippincott威廉姆斯&威尔金斯。
Background and objective Digoxin is a known substrate of ATP-binding cassette 1311 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population.Methods Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C -> T, 2677G -> T/A, and 3435C -> Twere assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders.Results Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18-0.21 mu g/l per additional Tallele). The association was even stronger for the 1236-2677-3435 TTT haplotype allele [0.26 mu g/l (95% Cl 0.14-0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects.Conclusion We found that the common ABCB1 1236C -> T, 2677G -> T and 3435C -> T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population. Pharmacogenetics and Genomics 18:299-305 (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.