药物转运蛋白相关单核苷酸多态性在中国汉族健康人群中的分布

Distribution of related single nucleotide polymorphisms of drug transporters in healthy Chinese Han population

目的研究中国汉族健康人群中药物转运蛋白相关单核苷酸多态性(SNP)的分布频率。方法用已建立的快速聚合酶链式反应(PCR)分型方法以及PCR测序对中国健康汉族志愿者有机阴离子转运多肽1B1(OATP1B1)、OATP1B3、有机阳离子转运体1(OCT1)、P-糖蛋白(P-gp)、多药耐药相关蛋白2(MRP2)以及乳腺癌耐药蛋白(BCRP)等6种药物转运蛋白的10个SNPs进行测定。计算等位基因分布频率,并与千人基因组计划中的不同人群比较等位基因频率的分布差异。结果 OATP1B1 388A>G、OATP1B1 521T>C、OATP1B3699G>A、OCT1 181C>T、OCT1 1393G>A、OCT1 1258del A、MDR1 3435T>C、MRP2-24C>T、BCRP 421C>A以及BCRP 376C>T的次要等位基因频率在中国汉族健康人中分别为26.97%,6.25%,23.91%,0,0,0,38.47%,18.52%,31.97%以及1.48%。试验组和非洲人群的等位基因分布频率比较,OATP1B3699G>A突变频率分别为76.09%,35.63%;MDR1 3435T>C突变频率分别为61.53%,85.02%;MRP2-24C>T突变频率分别为18.52%,3.10%;BCRP421C>A突变频率分别为31.97%,1.29%,差异均有统计学意义(P<0.05)。试验组和美国人群的等位基因分布频率比较,OATP1B1 388A>G突变频率分别为26.97%,47.26%;BCRP 421C>A突变频率分别为31.97%,14.12%,差异均有统计学意义(P<0.05)。试验组和欧洲人群的等位基因分布频率比较,OATP1B1 388A>G突变频率分别为26.97%,40.26%;OATP1B1 521T>C突变频率分别为6.25%,16.10%;OCT1 181C>T突变频率分别为0,6.26%;BCRP421C>A突变频率分别为31.97%,9.44%,差异均有统计学意义(P<0.05)。试验组和日本人群的等位基因分布频率比较,差异无统计学意义(P>0.05)。结论部分转运蛋白基因多态性存在显著的种族差异。分析药物代谢相关转运蛋白的基因多态性在中国人中的分布频率是指导临床用药的重要依据。

Objective To investigate the distribution of related singlenucleotide polymorphisms （SNPs） of drug transporters in healthy ChineseHan population. Methods 10 specific SNPs of 6 drug transporters, including organic anion transporting polypeptide IB1 （OATP1B1）, OATP1B3, organic cation transporter 1 （OCT1）, P- glycoprotein （P- gp）, muhidrug resistance protein 2 （MRP2） and breast cancer resistance protein （BCRP）, were determined in healthy Chinese Han volunteers by the established rapid polymerase chain reaction （PCR） methods and sequencing. Gene frequencies were calculated andcompared with other populations in the 1000 genomes project. Results The minor allele frequencies of OATP1BI 388A 〉 G, OATP1B1 521T 〉 C, OATP1B3 699G 〉 A, OCT1 181C 〉 T, OCT1 1393G 〉 A, OCTI 1258delA, MDRI 3435T 〉 C, MRP2 -24C 〉 T, BCRP 421C 〉 A and BCRP 376C 〉 T were 26. 97%, 6. 25%, 23.91%, 0, 0, 0, 38. 47%, 18. 52%, 31.97% and 1.48%, respectively. By comparing the distribution of allele frequencies between test group and Mriean, the frequencies of the OATP1B3 699G 〉 A variant alleles were 76. 09% and 35.63%, respectively; the frequencies of the MDR1 3435T 〉 C variant alleles were 61.53% and 85.02%, respectively ; the frequencies of the MRP2 - 24C 〉 T variant alleles were 18. 52% and 3. 10%, respectively; the frequencies of the BCRP 421C 〉 A variant alleles were 31.97% and 1.29%, respectively. And these differences were statistics, ally significant （P 〈 0. 05）. By comparing the distribution of allele frequencies between test group and American, the frequencies of the OATP1B1 388A 〉 G variant alleles were 26. 97% and 47. 26%, respectively; the frequencies of the BCRP 421C 〉 A variant alleles were 31.97% and 14. 12%, respectively. And these differences were statistically significant （P 〈 0. 05 ）. By comparing the distribution of allele frequencies between test group and European, the frequencies of the OATP1B1 388A 〉 G variant alleles were 26. 97% and40.26%, respectively; the frequencies of the OATP1B1 521T 〉 C variant alleles were 6.25% and 16. 10%, respectively; the frequencies of the OCT1 181C 〉 T variant alleles were 0 and 6. 26%, respectively; the frequencies of the BCRP 421C 〉 A variant alleles were 31.97% and 9. 44%, respectively. And these differences were statistically significant （ P 〈 0. 05）. There was no significant difference in the distribution of allele frequencies between test group and Japanese （P 〉 0. 05 ）. Conclusion Significant differences were observed in the distributions of some SNPs between Chinese and other populations. It is important to analyze the distribution of the related genetic polymorphisms of drug transporters in Chinese people to guide rational drug use in clinical.