Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene
Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene
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DOI：
10.1097/00008571-200308000-00006
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发表时间：
2003-08-01
期刊：
影响因子：
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通讯作者：
Clark, AG
中科院分区：
文献类型：
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作者：
Kroetz, DL;Pauli-Magnus, C;Clark, AG
目的越来越多的证据表明，ABCB 1（MDR 1）基因的多态性导致P-糖蛋白底物生物利用度和组织分布的个体间差异。本研究的目的是（1）鉴定和描述ABCB 1基因中的新变体，（2）了解ABCB 1在群体水平上的变异程度，（3）分析ABCB 1中的变异如何在单倍型中结构化，以及（4）功能上表征P-糖蛋白中最常见的氨基酸变化的影响。包括30个新的变异和13个编码氨基酸的变化，在247个不同种族的DNA样本的集合中被确定。这些变体包括64个统计推断的单倍型，其中33个占分析的染色体的92%。两种最常见的单倍型ABCB 1 *1和ABCB 1 *13在6个位点（3个内含子、2个同义和1个非同义）存在差异，并存在于36%的所有染色体中。在核苷酸和单倍型水平上检测到显著的群体亚结构。整个ABCB 1基因的连锁不平衡是显着的，特别是在ABCB 1 *13中发现的变异位点之间，并推断重组。在常见的ABCB 1 *13单倍型中发现的Ala 893 Ser变化不影响P-糖蛋白functions.Conclusion本研究代表了ABCB 1核苷酸多样性和单倍型结构在不同人群中的综合分析，并说明了单倍型因素在表征ABCB 1多态性的功能后果中的重要性。(C)2003年利平科特威廉姆斯威尔金斯。
Objectives There is increasing evidence that polymorphism of the ABCB1 (MDR1) gene contributes to interindividual variability in bioavailability and tissue distribution of P-glycoprotein substrates. The aim of the present study was to (1) identify and describe novel variants in the ABCB1 gene, (2) understand the extent of variation in ABCB1 at the population level, (3) analyze how variation in ABCB1 is structured in haplotypes, and (4) functionally characterize the effect of the most common amino acid change in P-glycoprotein.Methods and results Forty-eight variant sites, including 30 novel variants and 13 coding for amino acid changes, were identified in a collection of 247 ethnically diverse DNA samples. These variants comprised 64 statistically inferred haplotypes, 33 of which accounted for 92% of chromosomes analyzed. The two most common haplotypes, ABCB1*1 and ABCB1*13, differed at six sites (three intronic, two synonymous, and one non-synonymous) and were present in 36% of all chromosomes. Significant population substructure was detected at both the nucleotide and haplotype level. Linkage disequilibrium was significant across the entire ABCB1 gene, especially between the variant sites found in ABCB1*13, and recombination was inferred. The Ala893Ser change found in the common ABCB1*13 haplotype did not affect P-glycoprotein function.Conclusion This study represents a comprehensive analysis of ABCB1 nucleotide diversity and haplotype structure in different populations and illustrates the importance of haplotype considerations in characterizing the functional consequences of ABCB1 polymorphisms. (C) 2003 Lippincott Williams Wilkins.