HLA Class II associations with Crohn’s Disease
HLA-DRB1*07 and CARD15 negative ileal Crohn's disease
The most consistently replicated association of Crohn's disease with a common HLA allele is with HLA-DRB1*07. The population frequency of this allele varies between 5%-29% in Europeans and North Americans but is less than 1% in Japanese. The 1998 meta-analysis demonstrated a weak association of HLA-DRB1*07 in unselected patients with Crohn's disease (OR 1.42, CI 1.16-1.74)[14], but three subsequent studies of well-characterised patients from the UK (n = 244)[15], Canada (n = 432)[16] and Spain (n = 210)[17] showed that this association is specifically with patients with ileal involvement (with or without colonic disease). When comparison was made in these 3 studies between patients with, and patients without ileal disease, the Odd's Ratios for ileal disease were 1.5[15], 1.9[16] and 2.6[17] respectively, which are equivalent to those observed for possession of a single CARD15 variant. Importantly the UK and Canadian studies provided evidence for genetic heterogeneity in ileal Crohn's disease, by demonstrating that the association with HLA-DRB1*07 is only present in patients who do not possess one of the three common Crohn's disease associated CARD15 variants[15,16].
Studies in other ethnic groups have not been as detailed. Few Jewish patients were included in the UK or Spanish studies, but data from the Canadian study suggested that this phenotypic association may also be present in this ethnic group, although the relatively small number included prevented this reaching statistical significance[16]. DRB1*07 appears not to be associated with Crohn's disease in the Japanese, although studies have been insufficiently powered to detect a modest effect of such a rare allele.
HLA-DRB1*0103 and Colonic Crohn's disease
HLA-DRB1*0103 is a rare allele with a frequency of less than 2% in European and white North American populations. It is present at a similar frequency in Jews but is absent in the Japanese. A strong association of HLA-DRB1*0103 with ulcerative colitis was identified in 1996[12], but not demonstrated in Crohn's disease until 2000[18], almost certainly a consequence of the disease heterogeneity of Crohn's disease and the low prevalence of this allele. This association has been widely replicated since, although studies in Jewish patients have been inconsistent[16,18]. Association with this allele is observed both on the DRB1*0103-DQB1*0301 and DRB1*0103-DQB1*0501 haplotypes, strongly implicating DRB1*0103 in disease pathogenesis. It is now clear that DRB1*0103 is strongly associated with colonic location, particularly isolated colonic disease[15-17,19]. The Odd's ratios for isolated colonic disease range from 5.1 to 18.5 in non-Jewish caucasoids[15-17]. Data from a recent study suggests that amongst British patients with isolated colonic Crohn's disease, DRB1*0103 is associated with the development of severe disease as defined by the requirement for infliximab or colectomy. Furthermore data from this study suggests this allele may predict time to surgery (personal communication-Laura Hancock). Despite the strength of these associations it should be noted that this allele was present in no more than 32% of patients with isolated colonic disease, indicating that whilst this marker has a high positive likelihood ratio, the negative likelihood ratio limits its clinical application. Association with perianal location and fistulizing behaviour, reported in two studies, probably reflects their clinical association with colonic disease, rather than an independent genetic association[15,17].
HLA-DRB3*0301 - HLA-DRB1*1302
The HLA-DRB3 gene is expressed in less than 50% of Europeans and white North Americans, and has not been extensively studied in IBD. However, a meta-analysis of three studies, each comprising less than 70 patients, supports a positive association of Crohn's disease with DRB3*0301 (OR 2.18, CI 1.25-3.80)[14]. This association has been replicated in a larger cohort of British patients (RR = 2.4)[15], although once again inadequate sample size has prevented investigators determining whether it is due to linkage disequilibrium with another disease associated DRB1 allele, DRB1*1302[14,15], or the HLA class Ⅰ allele Cw*0802[15]. Although stratification by disease phenotype is limited, data from this latter study, which awaits replication, suggests that this association is most marked in patients with perianal disease.
HLA-DRB1*04 and CARD15 positive ileal disease?
Data from the meta-analysis of seven small studies also demonstrated a non-significant increase in the common allele HLA-DRB1*04 in Crohn's disease (OR 1.62 CI 0.73-3.61)[14]. This association is particularly important in Japanese cohorts, in whom the strongest HLA associations are with DRB1*0405, *0410, and the linked DQB1*0401, 0402 alleles[20-22]. Association with DRB1*04 has not been widely observed in European and North American patients. However in the recent Canadian study, a weak association with DRB1*04 was identified in patients with ileal disease RR = 1.7 (1.1-2.5)[16]. It is interesting that this association was stronger in patients possessing one of the three common Crohn's disease associated CARD15 variants, which may indicate an epistatic interaction between this DRB1 allele and CARD15 in determining susceptibility to ileal Crohn's disease[16]. Genotype-phenotype analysis of this allele in the Japanese is awaited.
HLA-DRB1*1501 – Crohn’s disease protection
Much confusion has surrounded associations of Crohn's disease with the serologically defined HLA allele DR2. DR2 includes the molecularly defined alleles HLA-DRB1*1501 and HLA-DRB1*1502, amongst others. The allele frequency of DRB1*1501 varies between 6%-25% in European and white North American populations and 6%-10% in the Japanese. It is negatively associated with Crohn's disease which explains the earlier negative association reported with the serological antigen DR2 (OR 0.83, CI 0.70-0.09) highlighted in the 1999 meta-analysis[14]. This allele appears to confer protection against all subgroups of Crohn's disease, in all ethnic groups including Japanese.
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