Tang Kun, Wong Li Peng, Lee Edmund J D, Chong Samuel S, Lee Caroline G L
Department of Biochemistry, National University of Singapore, Singapore.
Hum Mol Genet. 2004 Apr 15;13(8):783-97. doi: 10.1093/hmg/ddh099. Epub 2004 Feb 19.
The MDR1 multidrug transporter regulates the traffic of drugs, peptides and xenobiotics into the body as well as sensitive tissues like the brain, germ cells and the developing fetus. Hence, it may influence an individual's response to drugs as well as his/her susceptibility to complex diseases in which environmental factors, especially xenobiotics, play a role. Polymorphisms within this gene, especially single-nucleotide polymorphism e26/3435(C/T), have been variously associated with differences in MDR1 expression, function, drug response and disease susceptibility. Here, we report the detailed characterization of the haplotype and linkage disequilibrium architecture of the entire 200 kb of the MDR1 gene in five world populations, namely, Chinese, Malays, Indians, Caucasians and African-Americans. We observed varied haplotype diversity across the entire gene in the different populations. The major haplotype mh5, which contains the subhaplotype e12/1236T-e21/2677T-e26/3435T, is highly represented among the four non-African populations, while mh7, which contains the subhaplotype e12/1236C-e21/2677G-e26/3435C, accounts for over a third of African-American chromosomes. These observations are inconsistent with a simple population evolution model, but instead are suggestive of recent historical events that have maintained such long range linkage disequilibrium. Using a modified long-range haplotype test, we found statistically significant evidence of recent positive selection for the e21/2677T and e26/3435T alleles in the Chinese population, and for the e26/3435T allele in the Malay population. Interestingly, we also detected evidence for positive selection of the alternative allele e26/3435C in the African-American population. These data suggest that independent mutational events may have occurred on the mh5 and mh7 haplotypes of the MDR1 gene to confer positive selection in the non-African and African-American populations, respectively.
多药耐药蛋白1（MDR1）多药转运体调节药物、肽和外源性物质进入体内以及进入如大脑、生殖细胞和发育中的胎儿等敏感组织。因此，它可能影响个体对药物的反应以及其对复杂疾病的易感性，在这些复杂疾病中环境因素尤其是外源性物质起作用。该基因内的多态性，尤其是单核苷酸多态性e26/3435（C/T），与MDR1表达、功能、药物反应和疾病易感性的差异存在多种关联。在此，我们报告了五个世界人群（即中国人、马来人、印度人、高加索人和非裔美国人）中MDR1基因全长200 kb的单倍型和连锁不平衡结构的详细特征。我们在不同人群中观察到整个基因的单倍型多样性各不相同。主要单倍型mh5包含亚单倍型e12/1236T - e21/2677T - e26/3435T，在四个非非洲人群中高度富集，而包含亚单倍型e12/1236C - e21/2677G - e26/3435C的mh7在非裔美国人染色体中占比超过三分之一。这些观察结果与简单的群体进化模型不一致，反而提示了维持这种长程连锁不平衡的近期历史事件。使用改良的长程单倍型检验，我们发现有统计学显著证据表明中国人群中e21/2677T和e26/3435T等位基因近期受到正选择，马来人群中e26/3435T等位基因近期受到正选择。有趣的是，我们还检测到非裔美国人人群中替代等位基因e26/3435C受到正选择的证据。这些数据表明，MDR1基因的mh5和mh7单倍型上可能分别发生了独立的突变事件，从而在非非洲人群和非裔美国人人群中赋予正选择。
