Kroetz Deanna L, Pauli-Magnus Christiane, Hodges Laura M, Huang Conrad C, Kawamoto Michiko, Johns Susan J, Stryke Doug, Ferrin Thomas E, DeYoung Joseph, Taylor Travis, Carlson Elaine J, Herskowitz Ira, Giacomini Kathleen M, Clark Andrew G
Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0446, USA.
Pharmacogenetics. 2003 Aug;13(8):481-94. doi: 10.1097/00008571-200308000-00006.
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.
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, ABCB11 and ABCB113, 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 ABCB113, and recombination was inferred. The Ala893Ser change found in the common ABCB113 haplotype did not affect P-glycoprotein function.
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.
越来越多的证据表明，ABCB1（MDR1）基因多态性导致了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）鉴定并描述ABCB1基因中的新变异；（2）了解ABCB1基因在群体水平上的变异程度；（3）分析ABCB1基因变异在单倍型中的结构；（4）从功能上表征P-糖蛋白中最常见氨基酸变化的影响。
在247份不同种族的DNA样本中，鉴定出48个变异位点，其中包括30个新变异和13个编码氨基酸变化的位点。这些变异构成了64个经统计学推断的单倍型，其中33个占所分析染色体的92%。两个最常见的单倍型ABCB11和ABCB113在六个位点存在差异（三个内含子、两个同义突变和一个非同义突变），占所有染色体的36%。无论是在核苷酸水平还是单倍型水平，均检测到显著的群体亚结构。整个ABCB1基因的连锁不平衡显著，尤其是在ABCB113中发现的变异位点之间，并推断存在重组。在常见的ABCB113单倍型中发现的Ala893Ser变化不影响P-糖蛋白功能。
本研究对不同人群的ABCB1核苷酸多样性和单倍型结构进行了全面分析，说明了在表征ABCB1多态性的功能后果时考虑单倍型的重要性。
