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, whereas 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 affects 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. Although 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.