Does HLA determination have a role in clinical practice?
Clinical observation, supported by molecular and serological data, strongly suggests that IBD is a heterogeneous family of inflammatory disorders. Ultimately, it is hoped that more accurate clinical, serological and molecular definition of these disorders will lead to better understanding of the different biological mechanisms and complex environmental interactions specific to disease subgroups. This would assist clinicians in the prediction of disease course, prognosis, complications and response to therapy. The data reviewed in this report demonstrate that genes in the HLA are important in determining susceptibility and phenotype of Crohn's disease and ulcerative colitis. Although the specific disease causing gene(s) remain unidentified, the strength and consistency of the emerging HLA associations have confirmed the importance of classifying patients both by accurately defined clinical characteristics, and by possession of known genetic risk factors, such as CARD15 disease associated variants.
In both Crohn's disease and ulcerative colitis, the most consistently replicated associations are with the classical class Ⅱ gene, HLA-DR. In Crohn's disease the strongest associations are observed with subgroups defined by location of disease. No consistent associations have been reported with disease behaviour, a less stable phenotypic characteristic, or with age at diagnosis. At present, there is little information about HLA associations with complications or response to treatment in Crohn's disease. In ulcerative colitis, the strongest HLA associations are seen with overall susceptibility, which is consistently associated with two alleles, DRB1*0103 and DRB1*1502. These alleles vary widely in prevalence across ethnic groups. Fewer subgroup associations have been identified than with Crohn's disease, but the association with DRB1*0103 is particularly strong in patients with extensive or severe disease. However, the low sensitivity and specificity of these associations currently preclude their use as a tool in diagnosis of either Crohn's disease or ulcerative colitis. For the same reason, it is unlikely that the use of HLA markers alone will be useful in disease screening of asymptomatic, genetically high risk individuals.
In addition to the interest in using biomarkers to predict IBD susceptibility, there is also considerable interest in using molecular and serological markers to assist in the discrimination of Crohn's disease from ulcerative colitis. Currently, markers in the HLA cannot be reliably used for this purpose. Indeed the shared association of DRB1*0103 and B*52 with ulcerative colitis and colonic Crohn's disease suggests the presence of at least one shared HLA susceptibility factor, providing a tantalising clue as to the potential molecular basis for the definition of colonic inflammation. Such shared HLA factors may explain in part why both forms of IBD can coexist in a family at a frequency greater than expected by chance. The apparent differential effect of HLA-DRB1*0401, which is a susceptibility allele in Crohn's disease and a protective allele in ulcerative colitis is interesting, but weak, population specific, and neither sufficiently sensitive or specific to be clinically useful.
In the near future, knowledge of an individual's HLA genotype is likely to be most useful in the prediction of disease course in patients with an established diagnosis of Crohn's disease or ulcerative colitis. However, at present, the sensitivity and specificity of even the most robust associations limit their application in isolation in this clinical context. Integration of an individual's HLA genotype into a panel of other genetic and serological markers may improve the sensitivity and specificity, although ultimately this is likely to require the identification of the primary IBD genes within this complex region.
In common with virtually all other HLA associated complex diseases, the HLA susceptibility gene(s) for IBD remain elusive. This is a consequence of the obstacles that challenge the mapping of disease genes within this region, including the high gene density and degree of polymorphism; the complex haplotype structure and patterns of linkage disequilibrium; the relatively small relative risks conferred by disease associated alleles; and the likely clustering of more than one IBD susceptibility gene, either within the HLA, or within the surrounding IBD3 locus.
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