Received for publication June 8, 2007.
Revised October 11, 2007.
Accepted for publication October 15, 2007.

THE EFFECTS OF ABCB1 3’-UNTRANSLATED REGION VARIANTS ON mRNA STABILITY

Abstract

Genetic variation in ABCB1, encoding P-glycoprotein (P-gp), is a potential cause of interindividual variation in drug response. Numerous studies have focused on the effects of coding region variants on P-gp expression and function, while few noncoding region variants have been investigated. The 3'-untranslated region (UTR) regulates mRNA levels or stability via RNA-protein interactions with mRNA degradation machinery. mRNA stability is a key regulatory step controlling ABCB1 mRNA expression that ultimately impacts P-gp levels and function. We hypothesized that ABCB1 3'-UTR polymorphisms alter mRNA stability by disrupting RNA-protein interactions. An ethnically diverse panel of DNA samples was sequenced to identify 3'-UTR polymorphisms and determine allele frequencies. The three most common variants, along with reference ABCB1, were stably expressed in cells in order to measure mRNA half-life. The calculated half-life for ABCB1 reference in HEK293 cells was 9.4 ± 1.3 h and was similar to that estimated for the 3'-UTR variants. Endogenous ABCB1 mRNA decay was similar in lymphoblastoid cell lines carrying 3'-UTR variant and reference alleles. While the examined ABCB1 3'-UTR variants have no effect on ABCB1 mRNA stability, these data represent one of the first attempts to determine the influence of genetic variation in UTRs on ABCB1 mRNA levels.

Key words: ABC transporters, human genetics, p-glycoprotein, pharmacogenetics, polymorphisms