SERONEGATIVE ARTHRITIS (MA KHAN, SECTION EDITOR) Polymorphism of HLA-B27: 105 Subtypes Currently Known Muhammad Asim Khan Published online: 29 August 2013 # Springer Science+Business Media New York 2013 Abstract HLA-B27 has a high degree of genetic polymor- phism, with 105 known subtypes, named HLA-B*27:01 to HLA-B*27:106, encoded by 132 alleles. The most common subtypes associated with ankylosing spondylitis are HLA- B*27:05 (Caucasians), HLA-B*27:04 (Chinese), and HLA- B*27:02 (Mediterranean populations). For Chinese popula- tions, HLA-B*27:04 is associated with a greater ankylosing spondylitis risk than HLA-B*27:05. Two subtypes, HLA- B27*06 and HLA-B27*09, seem to have no disease associa- tion. These differential disease associations of HLA-B27 subtypes, and the recent discovery that ERAP1 is associat- ed with ankylosing spondylitis for patients with HLA-B27, have increased attempts to determine the function of HLA- B27 in disease pathogenesis by studying hemodynamic features of its protein structure, alterations of its peptidome, aberrant peptide handling, and associated molecular events. However, after 40 years we still do not fully know how HLA-B27 predisposes to ankylosing spondylitis and related spondyloarthritis. Keywords Ankylosing spondylitis . Spondyloarthritis . Spondyloarthropathies . HLA-B27 . Subtypes . HLA-B*27 . HLA-B*27:05 . Alleles . HLA-B*27:0502 . Pathogenesis . ERAP1 . Polymorphism . Genetic heterogeneity Introduction HLA-B27 is an HLA class I surface protein encoded at the B locus of the major histocompatibility complex (MHC), on the short arm of chromosome 6. It was discovered as a serological specificity in 1969 [1], and four years later its association with ankylosing spondylitis and related forms of spondyloarthritis was discovered [2–4]. It was later observed that the strength of this association varies for different forms of spondyloarthritis and between ethnic and racial groups [5–8]. Polymorphism of HLA-B27 Genes and Molecules Research has revealed HLA-B27, like many other HLA class I molecules, to have high genetic polymorphism. This poly- morphism largely results from nucleotide changes in exons 2 and 3, which encode the alpha 1 and alpha 2 domains of HLA- B27’ s antigen-binding cleft [9–11]. The number of known subtypes of HLA-B27 is now 105, named HLA-B*27:01 to HLA-B*27:106 by the new nomenclature (Fig. 1)[12]. There is no subtype HLA-B*27:22: this assignment was revoked when it was later found to be based on a sequence error. The HLA-B*27 gene has 132 currently-known alleles, de- fined on the basis of nucleotide sequence difference [12]. As shown in Fig. 1, there are two alleles for the HLA-B*27:02 subtype (HLA-B*27:0201 and HLA-B*27:0202), three alleles for HLA-B*27:04, 21 alleles for HLA-B*27:05, three alleles for HLA-B*27:07, and two alleles for HLA-B*27:90, making 131 alleles altogether [12]. HLA-B*27:0502 is the most wide- ly distributed allele, and is probably the ancestral allele from which the others evolved [10, 13•, 14]. Some alleles are caused by mutations that are located within introns and are therefore “silent”, or are in exons but do not cause amino acid changes. These “null” alleles, with the suffix ‘N’, are HLA-B*27:59N, HLA-B*27:64N, HLA- B*27:65N, HLA-B*27:66N, HLA-B*27:90N and HLA- B*27:94N [12]. HLA-B*27:13 differs from HLA-B*27:0502 only in the leader segment of the gene, which is not part of the expressed product: at the cell surface, the HLA-B27 molecule encoded by these two alleles is identical [10]. This article is part of the Topical Collection on Seronegative Arthritis M. A. Khan (*) MetroHealth Medical Center, Division of Rheumatology, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109-1998, USA e-mail: mkhan@metrohealth.org Curr Rheumatol Rep (2013) 15:362 DOI 10.1007/s11926-013-0362-y