Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects.
Interindividual epigenetic variation in ABCB1 promoter and its relationship with ABCB1 expression and function in healthy Chinese subjects.
复制标题
中国健康受试者ABCB1启动子个体间表观遗传变异及其与ABCB1表达和功能的关系。
DOI：
10.1111/bcp.12675
复制
发表时间：
2015-11
影响因子：
3.4
通讯作者：
Zhou Hong-Hao
中科院分区：
文献类型：
--
作者：
Wu Lan-Xiang;Wen Chun-Jie;Li Ying;Zhang Xue;Shao Ying-Ying;Yang Zhu;Zhou Hong-Hao
目的
个体间表观遗传变异可能是导致ATP结合盒亚家族B成员1（ABCB 1）表达和功能个体间变异的重要机制。本研究的目的是探讨ABCB 1启动子的个体间表观遗传变异对健康中国人ABCB 1表达和功能的影响。
方法
采用亚硫酸氢盐测序聚合酶链反应（PCR）和染色质免疫沉淀法，分析了157名健康男性志愿者粪便DNA和结肠脱落细胞中ABCB 1启动子的DNA甲基化和组蛋白乙酰化状态。实时荧光定量PCR检测结肠上皮细胞ABCB 1 mRNA水平。在具有不同表观遗传特征的受试者中，研究了地高辛（0.5 mg）单次口服给药后的地高辛药代动力学。
结果
粪便DNA中ABCB 1基因启动子甲基化水平在0.84%~ 18.05%之间存在显著个体差异。ABCB 1启动子的高甲基化水平与乙酰化组蛋白H3和ABCB 1 mRNA表达的低水平密切相关。在高甲基化组中，浓度-时间曲线下面积地高辛的AUC（0-4 h）和AUC（0-10 h）分别增加19% [95%置信区间（CI）10%，31%; P = 0.024]和13%（95% CI 8%，26%; P = 0.026），地高辛峰浓度（Cmax）较低甲基化组增加30%（95% CI 12%，41%; P = 0.021）。
结论
ABCB 1启动子的表观遗传修饰在中国健康受试者中表现出高度的个体间变异性，并且与ABCB 1 mRNA表达和地高辛0-4 h体内血浆浓度的个体间变异密切相关。
AIM
Interindividual epigenetic variation is likely to be an important mechanism contributing to the interindividual variability in the expression and function of ATP-binding cassette, sub-family B, member 1 (ABCB1). The aim of the present study was to explore the effect of interindividual epigenetic variability in the ABCB1 promoter on ABCB1 expression and function in healthy Chinese subjects.
METHODS
Using bisulfite sequencing polymerase chain reaction (PCR) and chromatin immunoprecipitation assays, the DNA methylation and histone acetylation status of the ABCB1 promoter in stool DNA and exfoliated colonic epithelial cells of 157 healthy Chinese male volunteers was analysed. ABCB1 mRNA levels in colonic epithelial cells were detected by real-time PCR. The digoxin pharmacokinetics in subjects with different epigenetic profiles was investigated after a single oral administration of digoxin (0.5 mg).
RESULTS
The methylation levels of ABCB1 promoter in stool DNA showed a significant interindividual variation, from 0.84% to 18.05%. A high methylation level of the ABCB1 promoter was closely related to the low levels of acetylated histone H3 and ABCB1 mRNA expression. In the high methylation group, the area under the concentration-time curves (AUC(0-4 h) and AUC(0-10 h) ) of digoxin was increased by 19% [95% confidence interval (CI) 10%, 31%; P = 0.024] and 13% (95% CI 8%, 26%; P = 0.026), respectively, and the peak concentration (Cmax ) of digoxin was increased by 30% (95% CI 12%, 41%; P = 0.021) compared with the low methylation group.
CONCLUSIONS
The epigenetic modifications of the ABCB1 promoter show high interindividual variability in healthy Chinese subjects, and are closely related to the interindividual variation in ABCB1 mRNA expression and digoxin 0-4 h plasma concentrations in vivo.
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影响因子：
3.9
作者：
C. Zimmermann;H. Gutmann;P. Hruz;J. Gutzwiller;C. Beglinger;J. Drewe
通讯作者：
C. Zimmermann;H. Gutmann;P. Hruz;J. Gutzwiller;C. Beglinger;J. Drewe
DOI：
10.1016/j.trsl.2014.02.003
发表时间：
2015-01
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
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作者：
Nilsson EE;Skinner MK
通讯作者：
Skinner MK
影响因子：
8.8
作者：
El-Khoury, V.;Breuzard, G.;Fourre, N.;Dufer, J.
通讯作者：
Dufer, J.
影响因子：
13.5
作者：
Meier, Yvonne;Pauli-Magnus, Christiane;Stieger, Bruno
通讯作者：
Stieger, Bruno
DOI：
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发表时间：
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期刊：
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