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首页> 外文期刊>Pharmacogenetics and genomics >Promoter polymorphisms and allelic imbalance in ABCB1 expression.
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Promoter polymorphisms and allelic imbalance in ABCB1 expression.

机译：ABCB1表达中的启动子多态性和等位基因失衡。

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OBJECTIVE: The ABCB1 (MDR1) gene, encoding the transporter P-glycoprotein, is known to act on a broad range of prescription medicines. For this reason a large number of studies have assessed the functional consequences of variation in this gene. Particular attention has focused on the ABCB1_3435C>T polymorphism, an exonic variant resulting in a synonymous change. This variant has been associated with mRNA, protein and serum levels, and with responses to a number of medicines. The results of association studies have, however, been variable and it is not currently clear whether this polymorphism is functional or is in linkage disequilibrium with functionally distinct alleles. RESULTS: To identify functional variation in the ABCB1 gene we assessed allelic imbalance by pyrosequencing cDNA from 80 lymphoblastoid B cell lines from the Centre d'Etude du Polymorphisme Humain (CEPH) collection, including 74 individuals heterozygous for 3435C>T. We found that the degree of ABCB1 allelic imbalance differed among B-cell lines. In an effort to fine-map variants that influence the proportion of the two allelic mRNA species we genotyped representative common variations near the 3435C>T polymorphism by using a tagging single nucleotide polymorphism (SNP) approach. In one approach, we assessed in segregating families the impact of cis-acting variants on mRNA levels by using allelic imbalance as the phenotype in a regression analysis that distinguishes the coupling arrangements (phase) among alleles. In a second approach, we assessed allelic imbalance levels in lymphoblastoid B-cell lines from unrelated HapMap individuals, and performed an association using tagSNPs in a 5-Mb region surrounding the gene. Two potential cis-acting variants, a promoter rs28656907/rs28373093 dinucleotide polymorphism (P=0.007) and the rs10245483 SNP (P=0.0003) located 2 Mb upstream from the gene, were predictors of ABCB1 expression. CONCLUSIONS: The study outlines a general experimental approach for fine mapping gene variants that influence mRNAexpression by using cultured cell lines.
机译：目的：编码转运蛋白P-糖蛋白的ABCB1（MDR1）基因可在多种处方药中起作用。因此，大量研究评估了该基因变异的功能后果。特别关注的是ABCB1_3435C> T多态性，这是导致同义变化的外显子变体。该变体与mRNA，蛋白质和血清水平以及对多种药物的反应有关。然而，关联研究的结果是可变的，目前尚不清楚这种多态性是否具有功能性或与功能上不同的等位基因连锁不平衡。结果：为了鉴定ABCB1基因的功能变异，我们通过焦磷酸多态性中心（CEPH）中心的80个淋巴母细胞B细胞系的焦磷酸测序来评估等位基因失衡，其中包括74个3435C> T杂合的个体。我们发现A细胞BBC1等位基因不平衡的程度有所不同。为了细化影响两个等位基因mRNA种类比例的变异，我们使用标记单核苷酸多态性（SNP）方法对3435C> T多态性附近的代表性常见变异进行了基因分型。在一种方法中，我们在回归分析中通过区分等位基因之间的偶联安排（阶段），使用等位基因失衡作为表型，在分离的家族中评估了顺式作用变体对mRNA水平的影响。在第二种方法中，我们评估了来自无关HapMap个体的淋巴母细胞B细胞系中的等位基因失衡水平，并使用围绕该基因的5-Mb区域中的tagSNP进行了关联。位于基因上游2 Mb的两个潜在的顺式作用变体，启动子rs28656907 / rs28373093二核苷酸多态性（P = 0.007）和rs10245483 SNP（P = 0.0003），是ABCB1表达的预测因子。结论：这项研究概述了通过使用培养的细胞系来精细定位影响mRNA表达的基因变异的一般实验方法。

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