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AAPS J. 2006 Sep; 8(3): E515–E520.
Published online 2006 Aug 18. doi:  10.1208/aapsj080361
PMCID: PMC2761059

Searching for polymorphisms that affect gene expression and mRNA processing: Example ABCB1 (MDR1)


Cis-acting genetic variations can affect the amount and structure of mRNA/protein. Genomic surveys indicate that polymorphisms affecting transcription and mRNA processing, including splicing and turnover, may account for main share of genetic factors in human phenotypic variability; however, most of these polymorphisms remain yet to be discovered. We use allelic expression imbalance (AEI) as a quantitative phenotype in the search for functionalcis-acting polymorphisms in many genes includingABCB1 (multidrug resistance 1 gene, MDR1, Pgp). Previous studies have shown that ABCB1 activity correlates with a synonymous polymorphism. C3435T; however, the functional polymorphism and molecular mechanisms underlying this clinical association remained unknown. Analysis of allele-specific expression in liver autopsy samples and in vitro expression experiments showed that C3435T represents a main functional polymorphism, accounting for 1.5-to 2-fold changes in mRNA levels. The mechanism appears to involve increased mRNA turnover, probably as a result of different folding structures calculated for mRNA with the Mfold program. Other examples of the successful application of AEI analysis for studying functional polymorphism include5-HTT (serotonin transporter, SLC6A4) andOPRM1 (μ opioid receptor). AEI is therefore a powerful approach for detectingcis-acting polymorphisms affecting gene expression and mRNA processing.

Keywords: ABCB1, allele-specific expression, mRNA stability, cis-acting polymorphism

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Selected References

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