Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects
Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects
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DOI：
10.1067/mcp.2001.114164
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发表时间：
2001-03-01
影响因子：
6.7
通讯作者：
Roots, I
中科院分区：
文献类型：
--
作者：
Cascorbi, I;Gerloff, T;Roots, I
背景资料：P-糖蛋白是多药耐药基因1（MDR 1）的基因产物，它不仅能产生多药耐药，而且对临床常用药物的生物利用度有重要影响。最近发现了MDR 1基因的多种多态性。第26外显子沉默突变（C3435 T）与肠道P-糖蛋白表达和地高辛口服生物利用度相关目的：建立一种简便、经济的MDR 1单核苷酸多态性基因分型方法，并在大样本志愿者中研究其等位基因频率分布。本研究采用聚合酶链反应和限制性片段长度多态性技术，对461名白色志愿者的MDRI主要等位基因的分布进行了检测。在第21号外显子中发现了5个氨基酸替换位点，等位基因频率分别为Asn 21 Asp 11.2%和Ser 400 Asn 5.5%。2677 G（56.4%）、2677 T（41.6%）和2677 A（1.9%），编码893 Ala、Ser或Thr。2例（0.2%）发现Gln 1107 Pro错义突变。内含子和沉默多态性的频率最高，C3435 T发生在53.9%的受试者杂合子，和28.6%的个人是纯合子携带者的3435 T/T与功能限制的P-glycoprotein.Conclusion：这项研究提供了第一个分析MDR 1变异基因型分布在一个大样本的白色受试者。它为大规模临床研究MDR 1等位基因变体对大量药物生物利用度的功能作用提供了基础。
Background: P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin.Objective: We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers.Methods: In this study, the distribution of the major MDRI alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism.Results: Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn, Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein.Conclusion: This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.