Jada Srinivasa Rao, Xiaochen Shu, Yan Liu Yan, Xiaoqiang Xiang, Lal Suman, Zhou Shu Feng, Ooi London Lucien, Chowbay Balram
Laboratory of Clinical Pharmacology, Division of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
Eur J Clin Pharmacol. 2007 Jun;63(6):555-63. doi: 10.1007/s00228-007-0285-5. Epub 2007 Apr 6.
The aim of this study was to characterize the population frequency of SLCO1B1 polymorphic variants in three distinct healthy Asian populations, namely Chinese (n = 100), Malay (n = 100) and Indian (n = 100), and to explore the association between haplotype-tagged single nucleotide polymorphisms (htSNPs) on hepatic SLCO1B1 mRNA expression.
The distribution of polymorphic variants in the SLCO1B1 gene at eight loci that spanned approximately 48 kb was investigated in the three different Asian ethnic groups and in 32 non-cancerous liver tissues from Chinese patients.
Of the 26 polymorphisms screened, we found eight polymorphic variants that differed in genotypic and allelic frequencies between the Chinese, Malay and Indian populations. Significant interethnic differences were observed in the genotype frequency distributions across the promoter SNP [g.-11187G>A (P = 0.030)] as well as three coding region SNPs [c.388G>A (P < 0.001); c.571T>C (P < 0.001); c.597C>T (P < 0.001)] in the healthy subjects. Haplotype analysis revealed 12 different haplotypes in both the Chinese and Malay populations and 18 haplotypes in the Indian population. In both the Malay and Indian populations, the htSNPs were c.388A>G, c.571T>C and c.597C>T, whereas in the Chinese population they were g.-11187G>A, c.388A>G and c.597C>T. The c.388A>G and c.597C>T htSNPs accounted for more than 70% of the variations between the three major haplotypes in each Asian ethnic group. In terms of the c.388A>G htSNPs, genotypic-phenotypic association analyses revealed that there was no effect on SLCO1B1 expression in hepatic tissues; in addition, no genotypic-phenotypic associations were evident with regards to the c.597C>T htSNP.
Future studies should investigate the phenotypic effects of the c.388A>G htSNP on the disposition of OATP1B1 substrates in Asian populations.
本研究旨在确定三种不同的健康亚洲人群，即中国人（n = 100）、马来人（n = 100）和印度人（n = 100）中溶质载体有机阴离子转运体家族成员1B1（SLCO1B1）多态性变体的群体频率，并探讨肝脏中SLCO1B1 mRNA表达上的单倍型标签单核苷酸多态性（htSNP）之间的关联。
在三个不同的亚洲种族群体以及来自中国患者的32个非癌肝组织中，研究了跨越约48 kb的8个位点的SLCO1B1基因多态性变体的分布。
在筛选的26种多态性中，我们发现8种多态性变体在中国人、马来人和印度人群体中的基因型和等位基因频率存在差异。在健康受试者中，启动子单核苷酸多态性[g.-11187G>A（P = 0.030）]以及三个编码区单核苷酸多态性[c.388G>A（P < 0.001）；c.571T>C（P < 0.001）；c.597C>T（P < 0.001）]的基因型频率分布存在显著的种族间差异。单倍型分析显示，中国和马来人群体中有12种不同的单倍型，印度人群体中有18种单倍型。在马来人和印度人群体中，htSNP为c.388A>G、c.571T>C和c.597C>T，而在中国人群体中，它们是g.-11187G>A、c.388A>G和c.597C>T。c.388A>G和c.597C>T这两个htSNP在每个亚洲种族群体的三种主要单倍型之间的变异中占比超过70%。就c.388A>G htSNP而言，基因型-表型关联分析显示其对肝组织中SLCO1B1表达没有影响；此外，关于c.597C>T htSNP也没有明显的基因型-表型关联。
未来的研究应调查c.388A>G htSNP对亚洲人群中有机阴离子转运多肽1B1（OATP1B1）底物处置的表型影响。
