Statins reduce cholesterol, prevent cardiovascular disease, and are among the most commonly prescribed medications in the world. Statin‐associated musculoskeletal symptoms (SAMS) impact statin adherence and ultimately can impede the long‐term effectiveness of statin therapy. There are several identified pharmacogenetic variants that impact statin disposition and adverse events during statin therapy. SLCO1B1 encodes a transporter (SLCO1B1; alternative names include OATP1B1 or OATP‐C) that facilitates the hepatic uptake of all statins. ABCG2 encodes an efflux transporter (BCRP) that modulates the absorption and disposition of rosuvastatin. CYP2C9 encodes a phase I drug metabolizing enzyme responsible for the oxidation of some statins. Genetic variation in each of these genes alters systemic exposure to statins (i.e., simvastatin, rosuvastatin, pravastatin, pitavastatin, atorvastatin, fluvastatin, lovastatin), which can increase the risk for SAMS. We summarize the literature supporting these associations and provide therapeutic recommendations for statins based on SLCO1B1, ABCG2, and CYP2C9 genotype with the goal of improving the overall safety, adherence, and effectiveness of statin therapy. This document replaces the 2012 and 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for SLCO1B1 and simvastatin‐induced myopathy.

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1x10-30). In cells over-expressing human or various mammalian orthologs of SLC22A24, we showed that steroid conjugates and bile acids were substrates of the transporter. Phylogenetic, genomic, and transcriptomic analyses suggested that SLC22A24 has a specialized role in the kidney and appears to function in the reabsorption of organic anions, and in particular, anionic steroids. Phenome-wide analysis showed that functional variants of SLC22A24 are associated with human disease such as cardiovascular diseases and acne, which have been linked to dysregulated steroid metabolism. Collectively, these functional genomic studies reveal a previously uncharacterized protein involved in steroid homeostasis, opening up new possibilities for SLC22A24 as a pharmacological target for regulating steroid levels.

Human multidrug and toxin extrusion member 1, MATE1 (SLC47A1), plays an important role in the renal and biliary excretion of endogenous and exogenous organic cations including many therapeutic drugs. In this study, we characterized the transcriptional effects of five polymorphic variants and six common haplotypes in the basal promoter region of MATE1 that were identified in 272 DNA samples from ethnically diverse U.S. populations. We measured luciferase activities of the six common promoter haplotypes of MATE1 using in vitro and in vivo reporter assays. Haplotypes that contain the most common variant (mean allele frequency in four ethnics: 0.322), g.−66T>C, showed a significant decrease in reporter activities compared to the reference. Two transcription factors, AP-1 and AP-2rep, were predicted to bind to the promoter in the region of g.−66T>C. Results from electrophoretic mobility shift assays showed that the g.−66T allele, exhibited greater binding to AP-1 than the g.−66C allele. AP-2rep inhibited the binding of AP-1 to the MATE1 basal promoter region, and the effect was considerably greater for the g.−66T>C. These data suggest that the reduced transcriptional activity of g.−66T>C results from a reduction in the binding potency of the transcriptional activator, AP-1, and an enhanced binding potency of the repressor, AP-2rep to the MATE1 basal promoter region. Consistent with the reporter assays, MATE1 mRNA expression levels were significantly lower in kidney samples from individuals who were homozygous or heterozygous for g.−66T>C in comparison to samples from individuals who were homozygous for the g.−66T allele. Our study suggests that the rate of transcription of MATE1 is regulated by AP-1 and AP-2rep and that a common promoter variant, g.−66T>C may affect the expression level of MATE1 in human kidney, and ultimately result in variation in drug disposition and response.

hydroxyethyl)-1piperazineethanesulfonic acid); IC 50 , concentration of a compound to inhibit half of the activity; Km, the concentration of substrates to reach half of the maximum uptake rate (Vmax); MPP + , 1-methyl-4-phenylpyridinium; OAT, organic anion transporter; OCT, organic cation transporter; OCTN, organic zwitterions/cation transporter; PEPT, peptide transporter; SLC, solute carrier; SLCO, solute carrier family of organic anion transporting polypeptides; SNP, single-nucleotide polymorphism.

The increasing availability of genotype data linked with information about drug-response phenotypes has enabled genome-wide association studies (GWAS) that uncover genetic determinants of drug response. GWAS have discovered associations between genetic variants and both drug efficacy and adverse drug reactions. Despite these successes, the design of GWAS in pharmacogenomics faces unique challenges. In this review we analyze the last decade of GWAS in pharmacogenomics. We review trends in publications over time, including the drugs and drug classes studied and the clinical phenotypes used. Several data sharing consortia have contributed substantially to the PGx GWAS literature. We anticipate increased focus on biobanks and highlight phenotypes that would best enable future pharmacogenomics discoveries.