PharmGKB summary: very important pharmacogene information for human leukocyte antigen B

The human leukocyte antigen B (HLA-B) gene is a member of the major histocompatibility complex (MHC), a region of the human genome located on chromosome 6. The MHC (also known as the human leukocyte antigen (HLA) complex) includes three subregions, designated as class I, class II and class III. Each of these subregions contains a variety of genes that mainly code for proteins involved in the immune system. HLA-B is part of the class I group, along with HLA-A and HLA-C, all three of which code for their eponymous proteins [1]. Class II genes include HLA-DR, HLA-DP and HLA-DQ [2], and class III genes include complement components and cytokines such as complement factor B (CFB) and members of the tumor necrosis factor (TNF) family [1, 3]. The MHC is a large region of the genome, and contains many other genes besides the ones listed above; please see Horton et al. [1] for more details. The HLA genes are important within the field of pharmacogenetics: variations within these genes have been associated with severe drug reactions, as well as changes in how well a patient responds to a drug. The HLA-B protein and the other class I group members are cell-surface molecules responsible for the presentation of endogenous peptides to CD8+ T-cells, and exist on almost all nucleated cells. This is in contrast to class II molecules, which display exogenous peptides to CD4+ T-cells, and are present only on antigen presenting cells (APCs) such as macrophages or dendritic cells [2, 4]. This presentation of peptides to T-cells assists in the recognition of pathogens [2]. As a class I molecule, most of the peptides that HLA-B presents come from the normal breakdown of host cellular proteins, and are recognized by the immune system as such (i.e. “self” peptides). However, when a cell becomes infected by a pathogen, the proteins presented will be from the pathogen and recognized as foreign or “non-self”. T cell antigen receptors (TCRs) on CD8+ cytotoxic T cells are responsible for this recognition, and will stimulate an immune reaction that destroys the cell [5]. Class I molecules are expressed in a codominant fashion, and humans inherit a set of HLA-A, B and C genes from each parent. Therefore, given allelic variations within these genes, up to six different class I molecules can be expressed on a cell surface. HLA-A, B and C are heterodimers consisting of an α chain, encoded by their respective genes, and a protein known as β2-microglobulin, which is encoded on chromosome 15. The α chain of HLA-B has four domains: one cytoplasmic, one transmembrane, one which binds to CD8+ cytotoxic T cells, and one which makes up a peptide-binding groove, where the presented peptide is nestled [5]. This peptide-binding region of the gene is highly polymorphic, and allelic differences between class I genes are often due to variations within this region [2, 5]. Indeed, allelic variants of class I genes can differ from one another by up to 20 amino acids. Peptides bind to the groove through interaction with specific amino acid residues, so any amino acid changes due to allelic variation may affect the peptide-binding specificity of a class I molecule [5] (class II molecules have more flexibility in peptide-binding; see Janeway et al. [5]). The type of extensive polymorphism seen in HLA genes allows a wide variety of peptides to be presented, and likely evolved in order to effectively combat pathogens [5]. In addition to affecting the peptides capable of being presented, allelic variants in the HLA-B gene have also been associated with susceptibility and resistance to numerous diseases, as well as adverse reactions to a wide range of pharmaceuticals. This makes HLA-B highly relevant to pharmacogenetic research. This Very Important Pharmacogene (VIP) summary on HLAB is available with interactive links to genetic variants and drugs on the PharmGKB website at http://www.pharmgkb. org/gene/PA35056. HLA-B allele frequencies and nomenclature Due to the highly polymorphic nature of class I genes, a large number of HLA-B alleles have been identified. Information on the frequencies of over 2800 HLA-B alleles in populations worldwide can be found at The Allele Frequency Net Database (http://www.allelefrequencies.net/) [6]; allele frequencies for specific polymorphisms will be discussed within relevant sections of this review. Systematic nomenclature for these alleles is invaluable given their quantity. The HLA nomenclature committee has provided a detailed nomenclature to this end, and comprehensive information on the allele naming process can be found at their website at http://hla.alleles. org [7]. Briefly, all HLA alleles receive at least a four-digit name consisting of two sets of two digits separated by a colon, such as HLA-B*57:01. The first set of digits before the colon describes the type, typically the antigen designation used to describe the HLA alleles prior to genetic sequencing. The second set of digits indicates the specific allele, numerically ordered based on when the DNA sequence was discovered; this set of digits describes nonsynonymous substitutions only [7, 8]. This paper will only refer to the first one or two sets of digits. However, longer names, up to four sets of digits separated by colons and possibly a letter suffix, can be assigned if more detail is necessary, such as type or location of nucleotide substitution (e.g. synonymous or intronic) or resultant protein expression (e.g. null protein or cytoplasmic protein); for more information on this process, please refer to the HLA nomenclature website (http://hla.alleles.org).