A number of important observations should be noted from the reported associations with HLA Class Ⅱ alleles described above. Firstly, the specific associations with Crohn's disease and ulcerative colitis are different, with the notable exceptions of the shared association of ulcerative colitis and colonic Crohn's disease with HLA-DRB1*0103 and HLA-B*52. Secondly it is clear that multiple alleles, rather than a single allele, may be associated with any specific phenotype. Whilst these associations may merely reflect linkage disequilibrium with a nearby gene, this observation supports peptide presentation as an explanation for these associations, and raises the possibility of a shared disease-associated epitope, as seen in rheumatoid arthritis[36]. Some associated class Ⅱ alleles do indeed share significant residue changes in the third hypervariable region, which forms part of the antigen binding domain. However these are not shared by all of the associated alleles, suggesting this hypothesis cannot entirely explain these associations. Thirdly, it is not known whether a gene dose effect operates, such that possession of two HLA risk alleles confers additional risk. To date studies in IBD have not been sufficiently powered to conclusively answer this question. Fourthly, whilst many of the associations appear to be robust, it is clear that the penetrance of the genotype is low, and the presence of a risk allele is neither necessary nor sufficient for disease to occur. Finally the reported associations vary with ethnicity and geographical location, reflecting genetic heterogeneity, prevalence of risk alleles in the background population, and population specific patterns of linkage disequilibrium across the HLA. This illustrates the importance of studying ethnically homogenous cohorts in order to prevent population stratification.
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