Molecular diversity of the HLA-B27 gene and its association with disease

Abstract The human major histocompatibility complex (MHC) class I gene HLA-B27 bears a striking association with ankylosing spondylitis and related spondyloarthropathies. This association transcends all ethnic and geographical boundaries. The primary function of HLA-B27 as an MHC class I protein is to form a complex with β2-microglobulin resulting in a structure that is capable of presenting short antigenic peptides for recognition by cytotoxic T lymphocytes. HLA-B27 represents a family of 23 closely related alleles (B (*) 2701-23) called subtypes of HLA-B27, most of which have evolved from B (*) 2705. Studies from different parts of the world reveal differences in the population distribution. HLA-B27 subtypes are characterized by nucleotide substitutions (mostly nonsynonymous) in exons 2 and 3 which encode α1 and α2 domains of the peptide binding groove respectively. Gene conversion, point mutation, genetic draft, and recombination events are various mechanisms leading to heterogeneity of HLA-B27 and its evolution. Clustering of differences in the C/F pockets of HLA-B27 influences the peptide binding. Thus variations in strength of disease association of various HLA-B27 subtypes may be due to differences in peptide interaction of HLA-B27 subtypes. Because the association between HLA-B27 and disease is not absolute, possible influence of other genes on disease susceptibility needs further investigation. In this regard, the role of several candidate genes that include non-B27 MHC genes, MHC-related genes, MHC genes involved in antigen processing and transplant, cytokine genes, and markers on other chromosomes may be important. Besides these significant developments, satisfactory answers to many unresolved issues are sought. Understanding the exact mechanism of the HLA-B27 and disease association is continuing to be a subject of many studies.