HLA-DRB1*0103 and severe, extensive ulcerative colitis
The most consistently replicated association of ulcerative colitis in European and American populations is with the rare allele HLA-DRB1*0103. Data from the Stokkers et al[14] meta-analysis, derived from only 3 studies, demonstrated a moderate association in unselected ulcerative colitis patients (OR 3.42 CI 1.52-7.69). Subsequent larger studies have confirmed this association in Spanish[23], North American[18], British[24]and Mexican cohorts[25]. This association is particularly strong in patients with extensive[24-27] or severe disease, as defined by the need for colectomy for failed medical therapy[24,25]. Amongst patients who require colectomy this allele may also be associated with a shorter mean time to surgery[24]. Once again, the frequency of this allele, even in the ulcerative colitis population, is too low to be clinically useful in predicting disease course.
HLA-DRB1*1502
HLA-DRB1*1502 is associated with ulcerative colitis in European[24], North American[18], Japanese[22,28] and Korean[29] populations. Although the background prevalence of this varies considerably, being highest in the Japanese (20%-25%) and lowest in Northern Europeans (less than 1%), the associated relative risk is similar in all populations (2-4.5). This interesting transracial concordance suggests this allele, or a nearby allele, is a true disease causing variant. This association is specifically with HLA-DRB1*1502, rather than HLA-DRB1*1501, and explains the earlier reported association with the serological antigen DR2 (OR 2.00, CI 1.52-2.63) highlighted in the 1999 meta-analysis[14]. These two alleles differ only at amino acid position 86 within pocket 1 of the peptide binding groove. At this position HLA-DRB1*1501 has a valine and DRB1*1502 (and DRB1*0103) a glycine. Limited data suggests HLA-DRB1*1502 is associated with extensive and intractable ulcerative colitis amongst Japanese[30], but not Korean patients[29].
In Japanese[31] and British UC patients[24], association has also been reported with HLA-B*52, the class Ⅰ allele found in linkage disequilibrium with HLA-DRB1*1502. However, studies have been insufficiently powered to determine which allele represents the primary association due to the highly conserved nature of this haplotype. Interestingly HLA-B*52, but not HLA-DRB1*1502, has also been shown to be associated with colonic Crohn's disease in these populations[15,32], providing further evidence of a shared genetic basis for ulcerative colitis and colonic Crohn's disease.
HLA-DRB1*04-ulcerative colitis protection
The common HLA-DRB1*04 allele is negatively associated with ulcerative colitis in Northern Europeans and Japanese populations, in contrast to the positive association in Crohn's disease. Data from the Stokkers meta-analysis of 15 studies demonstrated an Odd’s Ratio of 0.54 (CI 0.73-3.61) in ulcerative colitis[14]. In the British population, the protective effect of this allele is confined to the most prevalent subtype DRB1*0401, and only then, when present on the two locus haplotype DRB1*0401-DQB1*0301[24]. This suggests that either an interaction between DRB1*0401 and DQB1*0301 is important for disease protection, or, and perhaps more likely, that the true protective polymorphism is found nearby on the associated extended haplotype.
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