Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11 Hospital Drive, Singapore.
Br J Clin Pharmacol. 2012 Apr;73(4):606-18. doi: 10.1111/j.1365-2125.2011.04123.x.
SLCO1B3 is an influx transporter located at the hepatocyte basolateral membrane and it is involved in the uptake of a broad range of drug substrates including docetaxel. The pharmacogenetics of SLCO1B3 is not well characterized and previous in vivo and in vitro studies reported conflicting results with regards to the functional effects of the limited number of SLCO1B3 polymorphisms that were studied. Docetaxel displays a wide interindividual variability in its pharmacokinetics and pharmacodynamics and an understanding of SLCO1B3 pharmacogenetics might provide clinical benefits in guiding docetaxel dosing.
The SLCO1B3 gene was comprehensively screened in the local healthy Asian populations (n= 168). A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15 haplotype-tag SNPs (htSNPs) were identified. These htSNPs were profiled in a cohort of Chinese nasopharyngeal cancer (NPC) patients (n= 50). Genotypic-phenotypic analysis showed that a haplotypic construct comprising of four variants [IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and *347_*348insA] was the critical determinant of docetaxel disposition. This study suggests that the comprehensive screening and haplotypic linkage analysis of SLCO1B3 can better elucidate its pharmacogenetic effects on interpatient variability of docetaxel and other putative drug substrates. Further studies are warranted in cancer patients belonging to other ethnic groups. AIMS To completely screen the SLCO1B3 gene in three distinct healthy Asian populations (Chinese, Malay and Indian, n= 168) and investigate the influence of haplotype-tag SNPs (htSNPs) on docetaxel disposition in 50 nasopharyngeal carcinoma patients.
Genomic DNA of individuals was screened for SLCO1B3 polymorphisms by direct sequencing. htSNPs were derived based on the sequence clustering algorithm and profiled in the patients. Population based genetic association analysis was performed using Haplostats package implemented in R and PLINK.
A strong linkage disequilibrium pattern was detected across a total of 88 polymorphisms and 15-htSNPs were identified. The SLCO1B3 haplotypic region comprising seven htSNPs was found to be significantly associated with docetaxel clearance (P= 0.003). Conditional haplotype analyses revealed that the haplotypic constructs comprising the IVS4+76G>A, 699G>A(Met233Ile), IVS12-5676A>G, and 347_348insA polymorphisms were critical determinants of variability in docetaxel disposition [clearance and area under the plasma concentration-time curve (AUC(0,∞)): r(2) = 29% and 22%, respectively]. Patients harbouring the GAG347insA haplotype were significantly associated with a 30% decrease in clearance and a 40% increase in AUC(0,∞) of docetaxel compared with patients harbouring the reference haplotype, GGA347wt (P= 0.025 and 0.018, respectively). In contrast, a 50% higher clearance was observed in patients carrying the GAG*347wt haplotype compared with those with the reference haplotype (P= 0.002). The functional SLCO1B3 haplotypic constructs included the widely studied Met233Ile variant and *347_*348insA located in the putative miR-890 binding site in the 3'-untranslated region which may influence the transport characteristics of SLCO1B3.
This study highlights the importance of SLCO1B3 polymorphic variations in influencing docetaxel disposition in nasopharyngeal carcinoma patients.
SLCO1B3 是一种位于肝细胞基底外侧膜的流入转运体，它参与了广泛的药物底物的摄取，包括多西紫杉醇。SLCO1B3 的药物遗传学尚未得到很好的描述，以前的体内和体外研究报告了关于所研究的有限数量的 SLCO1B3 多态性的功能影响的相互矛盾的结果。多西紫杉醇在药代动力学和药效学方面表现出广泛的个体间变异性，了解 SLCO1B3 的药物遗传学可能为指导多西紫杉醇剂量提供临床益处。
全面筛查了当地健康亚洲人群（n=168）的 SLCO1B3 基因。总共检测到 88 个多态性和 15 个单倍型标签 SNP（htSNP），存在很强的连锁不平衡模式。这些 htSNP 被纳入中国鼻咽癌（NPC）患者队列（n=50）。基因表型分析表明，由四个变体组成的单倍型构建体 [IVS4+76G>A、699G>A（Met233Ile）、IVS12-5676A>G 和 *347_*348insA] 是决定多西紫杉醇处置的关键决定因素。本研究表明，对 SLCO1B3 的全面筛查和单倍型连锁分析可以更好地阐明其对多西紫杉醇和其他假定药物底物的个体间变异性的药物遗传学影响。在属于其他种族的癌症患者中需要进一步的研究。目的：全面筛查三个不同的健康亚洲人群（中国人、马来人和印度人，n=168）中的 SLCO1B3 基因，并研究单倍型标签 SNP（htSNP）对 50 例鼻咽癌患者多西紫杉醇处置的影响。
直接测序法筛查个体的 SLCO1B3 多态性。基于序列聚类算法衍生 htSNP，并在患者中进行分析。使用 R 和 PLINK 中实现的 Haplostats 软件包进行基于人群的遗传关联分析。
总共检测到 88 个多态性和 15 个 htSNP，存在很强的连锁不平衡模式。发现包含七个 htSNP 的 SLCO1B3 单倍型区域与多西紫杉醇清除率显著相关（P=0.003）。条件单倍型分析显示，包含 IVS4+76G>A、699G>A（Met233Ile）、IVS12-5676A>G 和 347_348insA 多态性的单倍型构建体是决定多西紫杉醇处置变异性的关键决定因素[清除率和血浆浓度-时间曲线下面积（AUC（0，∞））：r（2）分别为 29%和 22%]。与携带参考单倍型 GGA347wt 的患者相比，携带 GAG347insA 单倍型的患者多西紫杉醇清除率显著降低 30%，AUC（0，∞）增加 40%（P=0.025 和 0.018）。相比之下，携带 GAG*347wt 单倍型的患者多西紫杉醇清除率增加 50%（P=0.002）。功能 SLCO1B3 单倍型构建体包括广泛研究的 Met233Ile 变体和位于 3'-非翻译区假定 miR-890 结合位点的 *347_*348insA，可能影响 SLCO1B3 的转运特性。
本研究强调了 SLCO1B3 多态性变异在影响鼻咽癌患者多西紫杉醇处置中的重要性。
