Gene-Wide Characterization of Common Quantitative Trait Loci for ABCB1 mRNA Expression in Normal Liver Tissues in the Chinese Population

Weihua Shou,Dazhi Wang,Wei Huang,Jinxiu Shi,Beilan Wang,Kaiyue Zhang,Zhimin Wang,Qingyang Huang

doi:10.1371/journal.pone.0046295

Weihua Shou, Dazhi Wang + Show 6 more

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https://doi.org/10.1371/journal.pone.0046295

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Journal: PLoS ONE	Publication Date: Sep 26, 2012
Citations: 11	License type: CC BY 4.0

Affiliation: Chinese National Human Genome Center, Ruijin Hospital

Abstract

In order to comprehensively screen genetic variants leading to differential expression of the important human ABCB1 gene in the primary drug-metabolizing organ, ABCB1 mRNA expression levels were measured in 73 normal liver tissue samples from Chinese subjects. A set of Tag SNPs. were genotyped. In addition, imputation was performed within a 500 kb region around the ABCB1 gene using the reference panels of 1,000 Genome project and HapMap III. Bayesian regression was used to assess the strength of associations by compute Bayes Factors for imputed SNPs. Through imputation and linkage disequilibrium analysis, the imputed loci rs28373093, rs1002205, rs1029421, rs2285647, and rs10235835, may represent independent and strong association signals. rs28373093, a polymorphism 1.5 kb upstream from the ABCB1 transcription start site, has the strongest association. 2677 G>A/T and 3435C>T confer a clear gene-dosage effect on ABCB1 mRNA expression. The systematic characterization of gene-wide common quantitative trait loci associated with ABCB1 mRNA expression in normal liver tissues would provide the candidate markers to ABCB1-relevant clinical phenotypes in Chinese population.

Highlights

The adenosine 59-triphosphate-binding cassette transmembrane protein P-glycoprotein (P-gp, or multidrug resistance protein 1, MDR1) is encoded by human ATP-binding cassette, subfamily B, member 1 (ABCB1) gene, a well-studied membrane transporter [1,2]
ABCB1 mRNA expression levels varied by nearly three folds in our samples, and showed an approximately normal distribution (Figure S1)
We accessed the strength of association by computing Bayes factors (BFs), and more finely mapped common expression quantitative trait loci (eQTL) within a 500 kb region across the ABCB1 gene

Summary

Introduction

The adenosine 59-triphosphate-binding cassette transmembrane protein P-glycoprotein (P-gp, or multidrug resistance protein 1, MDR1) is encoded by human ATP-binding cassette, subfamily B, member 1 (ABCB1) gene, a well-studied membrane transporter [1,2]. The extensive spectrum of substrates as well as the ubiquitous tissue distribution suggests P-gp as an efflux transporter with important roles in absorption, distribution and excretion of drugs, endogenous and exogenous chemicals, as well as the contribution to disease susceptibility [2]. P-gp overexpression in the barrier or excretory tissues protects the body from harmful compounds, and yet limits the drug access to target tissues. ABCB1 gene, regulating the exposure to xenobiotics and carcinogens, is associated with the occurrences, development and histopathological features of a broad set of high-grade cancers, including renal epithelial tumors [8], colorectal cancer [9,10] and haematological malignancies [11]. Localized ABCB1 overexpression greatly contributes to the multidrug resistance, resulting in the low bioavailability of many therapeutic agents and unfavorable treatment outcomes for a variety of tumors, e.g. haematological malignancies [11,12]. The primary limitation to efficacy of the antineoplastic drug paclitaxel in drugresistant cancer cells is the overexpression of the ABCB1 gene [13]

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