Background and aims: The genetic contribution to inflammatory bowel disease (IBD) is under investigation. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and IBD. We investigated the association between an intercellular adhesion molecule 1 gene (ICAM-1) polymorphism located on chromosome 19p13 and IBD in a Japanese population. Methods: We compared 207 Japanese patients who had IBD (79 with Crohn's disease (CD); 128 with ulcerative colitis (UC)) with 103 unrelated Japanese controls. We determined R241G and K469E polymorphisms of the ICAM-1 gene using polymerase chain reaction (PCR) techniques. Results: Both frequency and carriage rate of the K469 allele were significantly higher in IBD patients than in controls (allelic frequency, p c =0.0026; carriage rate, p c =0.0034; odds ratio 2.59; 95% confidence interval 1.42-4.68). Furthermore, the frequency of the K469 allele was significantly increased in both CD and UC. Subgroup analysis demonstrated that both K469 allelic frequency and K469 carriage rate were significantly higher in patients with the small bowel and colon type of CD and entire colitis compared with healthy controls. Conclusions: We identified an overall association between IBD and ICAM-1 K469 in a Japanese population. Further studies of this chromosome region are required to elucidate the gene responsible for IBD.

Major histocompatibility complex (MHC) class I chain-related gene A (MICA) has been found near the HLA-B gene. The MICA molecule is exclusively expressed on gastrointestinal epithelium and recognized by intestinal epithelial gamma delta T cells, where it exhibits a triplet repeat polymorphism in the transmembrane region. We investigated the possible correlation between MICA genetic polymorphism and ulcerative colitis (UC). Eighty-three patients with UC and 132 unrelated controls were included in this study. All subjects were Japanese. A triplet repeat polymorphism in the transmembrane region of the MICA was determined by direct sequencing procedures after amplification by a polymerase chain reaction. A significantly higher allele and phenotype frequencies of MICA A6 allele were observed in patients with UC than controls (allele frequency: P(c)=0.000011, phenotype frequency: P(c)=0.0049 odds ratio=2.62). A6 homozygous patients with UC showed significantly earlier onset of UC than patients without the A6 allele ((P)c=0.0042). Phenotypes of MICA A6 allele in Japanese are closely related to the disease susceptibility and behavior in UC. Examinations of MICA polymorphism in other ethnic groups may provide important information about the locus of primary responsible gene for UC.

We previously reported a conserved haplotype of HLA B52-DR2 and a significantly high frequency of the major histocompatibility complex (MHC) class I chain-related gene A (MICA) transmembrane-short tandem repeat (TM-STR) 6 allele in Japanese patients with ulcerative colitis (UC). To examine the predominance of the MICA TM-STR 6 allele as a marker of the susceptibility to UC within the susceptible haplotype, the association of each allele with UC was estimated following stratification of the patients to control for any possible confounding effects of other alleles positively associated with UC. Sixty-four patients with UC and 236 unrelated healthy controls were included in this study. All subjects were Japanese. HLA-A, -B, -C, and -DR antigens were determined serologically. A triplet repeat polymorphism of the MICA was determined by direct sequencing. To control for the effect of linkage disequilibrium, Mantel-Haenszel weighed odds ratios were calculated. Significantly higher phenotype frequencies of B52, MICA TM-STR 6, and DR2 were observed in patients with UC. Linkage disequilibria among alleles associated with UC revealed that a B52 - MICA TM-STR 6 - DR2 haplotype was conserved in patients with UC, as in controls. When the association of HLA-B52 was estimated after patient stratification for the possible confounding effect of MICA TM-STR 6 or DR2, a strong significant association of B52 with UC was still observed. In contrast, no association with UC was observed for MICA TM-STR 6 or DR2, after stratification of the possible confounding effect of HLA-B52. These results imply that the significant increase in MICA TM-STR 6 in Japanese patients with UC is attributable to linkage disequilibrium with HLA-B52.

Background/Aims: We investigated the mRNA expression of spectrum of cytokines in the colonic mucosa in inflammatory bowel disease (IBD). Methods: The expression of cytokine gene was evaluated by using the reverse transcription-polymerase chain reaction and the radioactivity of amplified cDNA standardized by coamplified β-actin cDNA. Results: Crohn’s disease and ulcerative colitis showed significantly increased expression of IL-1β, IL-6, IL-8 and TNF-α mRNA as compared with controls (p < 0.05). Conclusion: Proinflammatory cytokines such as IL-1β, IL-6, IL-8 and TNF-α are closely involved in the immune abnormalities of inflammatory mucosal lesions in IBD.

A decrease in the ratio of IL-1ra/IL-1β produced regionally by the colonic mucosa of patients with ulcerative colitis (UC) is believed to play a role in the pathogenesis of UC. To investigate factors influencing intramucosal IL-1ra/IL-1β ratios, we evaluated polymorphism of the IL-1ra gene and the production of mucosal cytokines in Japanese patients with UC. Colonic biopsy specimens of mucosal tissue were placed in organ cultures for 24 h. Then, the supernatant concentrations of IL-1β, IL-1ra, IL-8, IL-4, IL-10, and TGF-β were assayed by ELISA. Genomic DNA was extracted from patient peripheral blood samples, then IL-1ra gene polymorphism was determined using PCR amplification. The mucosa from patients with active stage UC showed a tendency toward a decreased IL-1ra/IL-1β ratio. In the resolving stage, IL-1ra/IL-1β ratios increased with increasing IL-10 and TGF-β concentrations. The addition of human recombinant IL-10 to the culture supernatants produced concentration-dependent inhibition of IL-1β. In Japanese patients with UC, the IL-1ra allele gene 2 phenotype had no effect on the IL-1ra/IL-1β ratio. Our findings suggest that a relative deficiency of IL-10 in patients with UC may contribute to persistent inflammatory changes.