PharmVar GeneFocus: SLCO1B1

Abstract

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms.

Figure 1. Overview of the gene locus and allelic variation

The SLCO1 gene locus contains four genes, SLCO1B3, SLCO1B7, SLCO1B1 and SLCO1A2. All but the latter are encoded by the positive strand (orientation is indicated by white arrows). The length of each gene and respective intergenic regions are shown in kilobase pairs (kb). SLCO1B1 comprises 15 exons (shown in approximate scale by individual blue boxes). 5’ and 3’ untranslated regions (UTRs) are highlighted in light blue. Regions affected by large deletion events are depicted by purple bars with whiskers indicating additional regions that may also be deleted; as shown, SLCO1B1 exons 1 through 7 may be affected by partial deletion; large events encompass the entire SLCO1B1 gene as well as its neighboring genes.

Figure 2. Overview of core allele and suballele categorization

Panel (a) is an excerpt of the SLCO1B1 gene page showing SLCO1B1*5, *15 and *46 allele definitions with NM_006446.5 as the reference sequence; their respective core allele definitions are depicted by gray bars. Core variants, PharmVar ID (PVID), and haplotype evidence levels are shown for each allele; their respective suballeles are displayed underneath the core allele bar. Legacy allele designations are cross-referenced, e.g., alleles originally defined as SLCO1B1*15A, *15B and *17 were consolidated into *15.001. Panel (b) is a graphical representation of selected alleles with their respective core variants of which those highlighted in red have been associated with decreased function. Blue boxes represent exons; untranslated regions are shown in light blue. Panel (c) represents the graphical output of the Comparative Allele ViewEr (CAVE) for ten selected star alleles. The PharmVar symbols indicate that the variant is unique to the allele and the function symbol signifies that the variant alters function. Since impact of c.1007C>G (P336R) remains unknown, this variant found in SLCO1B1*47 does not have the symbol indicating changed function.

Figure 3. Selected PharmVar submission exemplifying methods and approaches used to fully characterize SLCO1B1 allelic variants

Panels (a-c) provide examples of alleles submitted to PharmVar. Several provide additional information to substantiate existing allele definitions (e.g., SLCO1B1*15.002 and *20.001) while others represent a novel haplotype (*40.001), haplotypes previously published but not under a star name (*39.001 and *40.001), or novel suballeles (e.g., *20.002). Boxes represent the SLCO1B1 gene and black and red lines denote the variants found on each haplotype of a sample. Panel (a) exemplifies haplotypes that can unequivocally be deduced as only a single variant is heterozygous. Panel (b) shows haplotypes which were resolved using 10x Genomics Long Read data; each of the examples has two heterozygous variants that were mapped in trans (i.e., on opposite chromosomes). Panel (c) illustrates the characterization of four haplotypes using inheritance. Two subjects of this trio possess a rare haplotype, SLCO1B1*46. This allele has c.1738C>T (p.R580X) in addition to c.521T>C (p.V174A). As described in the text, c.1738C>T is in a region with less than average read coverage and exhibited allelic imbalance which may prevent accurate variant calling.