The human leucocyte antigen (HLA) complex is a highly polymorphic, gene dense region on chromosome 6p21.3 (Figure 1). The complex spans -4 Mb and encompasses at least 130 expressed genes[1,2]. These include the highly polymorphic classical class Ⅰ and Ⅱ HLA genes essential for normal lymphocyte function, and a number of other genes with immunoregulatory function. Since the first report of an HLA association with IBD in 1972, more than 100 studies have been published investigating the role of HLA genes in determining susceptibility and phenotype of inflammatory bowel disease (IBD). Early data derived from both association and linkage analyses were inconsistent, reflecting the difficulties of inadequate sample size, low resolution typing techniques, poor statistical methodology and a failure to consider disease heterogeneity. However, since the mid-1990's, advances in genotyping and computational technology, combined with improved study design, have been successfully applied to much larger, more accurately characterised cohorts of patients, and this has revealed important clues to molecular pathogenesis of IBD.
Genome-wide scans have shown consistent evidence of linkage to IBD3 (6p21.1-23), an area which encompasses the HLA complex. This has been demonstrated in several independent studies of both Crohn’s disease[4-8] and ulcerative colitis[5-8], and was recently been confirmed by the IBD Consortium in a large replication study of 733 nuclear families. The importance of this area was further highlighted by a meta-analysis of 10 published genome-wide scans. Notably in this study, IBD3 was the only locus that met genome-wide significance, and provided stronger evidence of linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. Although it is difficult to estimate the importance of this region in determining overall genetic susceptibility, calculations derived from studies of HLA allele sharing within families suggest that this region contributes between 10%-33% of the total genetic risk of Crohn's disease and 64%-100% of the total genetic risk of ulcerative colitis.
Interest in the HLA complex in IBD has traditionally focused on association with the classical class Ⅱ HLA alleles, but recent insights into the biological function of other genes encoded within this region have led investigators to a more diverse exploration of this region.