Abstract
Genetic variation in the expression of human xenobiotic metabolism enzymes and transporters (XMETs) leads to inter-individual variability in metabolism of therapeutic agents as well as differed susceptibility to various diseases. Recent expression quantitative traits loci (eQTL) mapping in a few human cells/tissues have identified a number of single nucleotide polymorphisms (SNPs) significantly associated with mRNA expression of many XMET genes. These eQTLs are therefore important candidate markers for pharmacogenetic studies. However, questions remain about whether these SNPs are causative and in what mechanism these SNPs may function. Given the important role of microRNAs (miRs) in gene transcription regulation, we hypothesize that those eQTLs or their proxies in strong linkage disequilibrium (LD) altering miR targeting are likely causative SNPs affecting gene expression. The aim of this study is to identify eQTLs potentially regulating major XMETs via interference with miR targeting. To this end, we performed a genome-wide screening for eQTLs for 409 genes encoding major drug metabolism enzymes, transporters and transcription factors, in publically available eQTL datasets generated from the HapMap lymphoblastoid cell lines and human liver and brain tissue. As a result, 308 eQTLs significantly (p < 10−5) associated with mRNA expression of 101 genes were identified. We further identified 7,869 SNPs in strong LD (r2 ≥ 0.8) with these eQTLs using the 1,000 Genome SNP data. Among these 8,177 SNPs, 27 are located in the 3′-UTR of 14 genes. Using two algorithms predicting miR-SNP interaction, we found that almost all these SNPs (26 out of 27) were predicted to create, abolish, or change the target site for miRs in both algorithms. Many of these miRs were also expressed in the same tissue that the eQTL were identified. Our study provides a strong rationale for continued investigation for the functions of these eQTLs in pharmacogenetic settings.
Highlights
Xenobiotic metabolizing enzymes and transporters (XMETs) are involved in biotransformation and detoxification of carcinogens, environmental toxins, and therapeutic drugs (Carlsten et al, 2008; Korkina et al, 2009)
GENOME-WIDE expression quantitative traits loci (eQTL) ANALYSIS OF XMETs Expression quantitative traits loci were screened for all 409 major XMET genes, including 144 phases: modification (phase I), 85 phase II and 111 phase III genes, 48 nuclear receptors (NRs), and transcription factor genes as well as another 21 genes related to drug ADME (Table A1 in Appendix)
Among the total of 308 eQTLs, 20 single nucleotide polymorphisms (SNPs) were found to be located in the 3 -UTR region; 3 SNPs were in the 5 -UTRs; 3 http://cbdb.nimh.nih.gov/microsniper 4 http://compbio.uthsc.edu/miRSNP/ 5 http://www.TargetScan.org/
Summary
Xenobiotic metabolizing enzymes and transporters (XMETs) are involved in biotransformation and detoxification of carcinogens, environmental toxins, and therapeutic drugs (Carlsten et al, 2008; Korkina et al, 2009). Many XMETs are found to be very abundant in non-digestive tract tissues/cells, e.g., brain, lung, bladder, and blood (Pavek and Dvorak, 2008). These XMETs could affect the local response to certain drugs at the site of action. Due to the crucial role of XMETs in detoxification of carcinogens and toxins, genetic variation in XMETs function in specific tissues/organs is an important mechanism underlying genetic susceptibility to certain diseases, e.g., those XMETs expressed in lung and bladder may modify cancer risk. These trans-acting regulators play a pivotal role in mediating cellular response to exposure to xenobiotics by modulating the transcription of XMETs, significantly contributing to the variability in the function of XMETs (Bourgine et al, 2012)
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