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Methods to Discover Alternative Promoter Usage and Transcriptional Regulation of Murine Bcrp1
Published on: May 27, 2016
Promoter polymorphisms and allelic imbalance in ABCB1 expression
Corinne Loeuillet1, Michael Weale, Samuel Deutsch
1Institute of Microbiology, University Hospital, Lausanne, Switzerland.
Pharmacogenetics and Genomics
|December 14, 2007
Summary
Researchers identified genetic variations influencing ABCB1 gene expression, impacting drug transporter P-glycoprotein levels. This study clarifies the functional role of ABCB1 gene variants and their association with drug response.
Area of Science:
- Pharmacogenomics
- Molecular Biology
- Genetics
Background:
- The ABCB1 gene encodes P-glycoprotein, a transporter affecting numerous medications.
- The ABCB1_3435C>T polymorphism has been linked to varying mRNA, protein, and serum levels, but its functional significance remains unclear.
- Previous association studies yielded inconsistent results regarding the ABCB1_3435C>T polymorphism's functionality or linkage disequilibrium with other alleles.
Purpose of the Study:
- To identify functional genetic variations within the ABCB1 gene.
- To investigate the impact of cis-acting variants on ABCB1 mRNA expression levels.
- To refine the mapping of variants influencing ABCB1 mRNA expression.
Main Methods:
- Assessed allelic imbalance in cDNA from 80 lymphoblastoid B cell lines using pyrosequencing.
- Genotyped common variations near the ABCB1_3435C>T polymorphism using a tagging single nucleotide polymorphism (SNP) approach.
- Employed regression analysis in segregating families and association studies in HapMap individuals to identify cis-acting variants.
Main Results:
- Significant differences in ABCB1 allelic imbalance were observed among B-cell lines.
- Two cis-acting variants, a promoter dinucleotide polymorphism (rs28656907/rs28373093) and SNP rs10245483, were identified as predictors of ABCB1 expression.
- The rs10245483 SNP, located 2 Mb upstream, showed a strong association with ABCB1 expression (P=0.0003).
Conclusions:
- The study presents a novel experimental approach for fine-mapping gene variants that affect mRNA expression.
- Identified specific genetic variants that influence ABCB1 gene expression.
- Provides a foundation for understanding the functional impact of ABCB1 genetic variation on drug response.
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