Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (antineutrophil cytoplasmic antibodies) markers.

Abstract

Newly described distinct associations of HLA class II genes with ulcerative colitis (UC) (DR2) and Crohn's disease (CD) (DR1 /DQ5) provide strong evidence for genetic heterogeneity of susceptibility between these two forms of inflammatory bowel disease. A familial distribution of antineutrophil cytoplasmic antibodies (ANCAs, a subclinical marker of UC) in UC families has further implied the existence of heterogeneity within UC.To test the hypothesis that the heterogeneity within UC indicated by ANCAs has a genetic basis that resides within the HLA region, we studied 89 UC cases and an ethnically matched control group (n = 50). Serological and molecular typing techniques were applied to define HLA class II genes (DR, DQ). ANCAs were detected using an enzyme-linked immunosorbent assay, and positive values were confirmed by indirect immunofluorescence.We observed that ANCA-positive UC patients (n = 70) had a significantly increased frequency of DR2 compared with ANCA-negative controls (n = 46) (44% vs 22%, P = 0.01). In contrast, the frequency of DR2 in ANCA-negative UC cases (21%) was virtually identical to that in controls (22%, P = 0.9). Furthermore, the ANCA-negative UC patients had an increase in the DR4 allele compared with ANCA-positive UC (P = 0.004).Thus, with the combination of a subclinical marker (ANCAs) and molecular genetic markers, genetic heterogeneity has been demonstrated within UC: ANCA-positive UC associated with DR2, and ANCA-negative UC likely associated with DR4. (J. Clin. Invest. 1993Invest. . 92:1080Invest. -1084

HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish Caucasian populations

“…Our previously reported association of DR1-DQ5 with CD [12,15,19,26] occurred as a trend in the present study (OR = 1.5, p = 0.068). However, the DR1 association was found attributable to the subtype DRB1*0103 in the combined Caucasian group of IBD patients, and this subtype was also significantly associated with both CD and UC patients (IBD: OR = 4.6, p = 0.001; CD: OR = 4.4, p = 0.002; and UC: OR = 4.9, p = 0.001).…”

“…For example, from earlier investigations using serologic methods, the frequency of the HLA class II serotype was increased in UC patients versus controls in most but not all European and United States Caucasian populations [7,13,15,[19][20][21][22]. In an English population study using DNA typing methods Satsangi et al found no association with DR2 in CD or UC patients [14].…”

“…To increase our understanding of the etiology and pathogenesis of various forms of IBD, we performed molecular HLA class II analysis (DRB1-DQB1-DPB1) on a large number of samples from both Jewish (Ashkenazi) and non-Jewish Caucasian subjects with IBD (CD, UC, or IBD indeterminate), and ethnically matched, normal control subjects. In our previous studies, we performed overall HLA disease association analyses with IBD [19,26,29]. The results of these studies suggested that particular HLA class II alleles or serogroups were associated with IBD.…”

NOD2 gene mutations in ulcerative colitis: useless or misunderstood?

“…NOD2, the first gene linked with increased susceptibility to CD, has later been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49]. Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) were also identified as being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

“…Among the UC susceptibility genes, HLA DRB1*0103 and the multidrug resistance gene 1 (MDR1/ABCB1) also contribute to clinical phenotype and natural history, being associated with extensive and severe disease [17,[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. In CD, NOD2 gene mutations have repeatedly been shown to be associated with ileal disease, early age of onset, stricturing, and/or penetrating phenotype and increased need for surgery [5,9,10,[38][39][40][41][42][43][44][45][46][47][48][49].…”