Journal
AAPS JOURNAL
Volume 8, Issue 3, Pages E515-E520Publisher
AMER ASSOC PHARMACEUTICAL SCIENTISTS
DOI: 10.1208/aapsj080361
Keywords
ABCB1; allele-specific expression; mRNA stability; cis-acting polymorphism
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Funding
- NIDA NIH HHS [DA018744] Funding Source: Medline
- NIGMS NIH HHS [GM61390] Funding Source: Medline
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U19GM061390, U01GM061390] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R21DA018744] Funding Source: NIH RePORTER
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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 the 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 functional cis-acting polymorphisms in many genes, including ABCB1 (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 mechanism 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 include 5-HTT (serotonin transporter, SLC6A4) and OPRM1 (mu opioid receptor). AEI is therefore a powerful approach for detecting cis-acting polymorphisms affecting gene expression and mRNA processing.
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