Genetic polymorphisms of P-glycoprotein: Echoes of silence

ABCB1 is a polymorphic gene that encodes a full ABC transporter with drug-binding pockets and two nucleotide-binding ATPase domains. It was one of the first members of the ABC transporter superfamily to be identified in humans. Since the discovery of this gene nearly 40 years ago, many mutations and polymorphisms in the coding region have been shown to have functional significance. Common genetic variations in the form of single nucleotide polymorphisms (SNPs) of ABCB1 have been shown to have a role in disease susceptibility and drug response. In this chapter, we summarize our current understanding of common ABCB1 SNPs and their impact on protein folding, drug transport function, disease risk factors, and drug pharmacokinetics. Unfortunately, clinical studies on the association of drug effects and ABCB1 polymorphisms are often inconclusive. In the past few years, meta-analyses of ABCB1 polymorphism studies have been carried out in attempts to draw more consistent conclusions. Among ABCB1 SNPs, the synonymous C3435T polymorphic site is perhaps one of the best-known silent mutations in the field of pharmacogenomics. Our current understanding of the mechanism of the effect of this “silent” SNP is discussed here. Overall, research efforts in the past 15 years have laid important groundwork concerning the effect of ABCB1 variants that should lead to advances in precision medicine in the future.