Hiroyuki Aihara

CARD15/NOD2 mutational analysis in Japanese patients with Crohn's disease

To the Editor: Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract and is considered to be a complex, multifactorial disease partly determined by a genetic predisposition. Among the putative CD-susceptibility loci, the pericentromeric region of chromosome 16, designated as IBD1, is most widely and consistently confirmed in Western populations (1, 2). Recently, three independent studies, one from the United States (3) and two from Europe (4, 5), have demonstrated that the three main variants (R702W, G908R, 3020insC) of CARD15/NOD2 (CARD15), located on chromosome 16q12, are associated with CD. In Japanese patients with CD, however, a genome-wide linkage analysis has not yet been performed and our collaborative research could not find any of the main variants of CARD15 (6). As our previous collaborative research was limited to

Lack of association between IBD5 and Crohn's disease in Japanese patients demonstrates population-specific differences in inflammatory bowel disease

Objective. Population-specific differences in the genetic susceptibility to inflammatory bowel disease (IBD) are indicated by the fact that Crohns disease (CD) in Japanese patients does not have any of the common CARD15 variants that are associated with CD in Caucasians. Recently, the disease-causing mutation in the IBD5 haplotype was identified. The TC haplotype, composed of L503F in SLC22A4 and −207G/C in SLC22A5 promoters, was reported to alter the function of the organic cation transporter and to be associated with CD in Caucasians. To determine whether the TC haplotype is also associated with IBD in a Japanese population, we genotyped L503F and −207G/C variants in Japanese subjects. Furthermore, we also performed a case-control association study with all representative single nucleotide polymorphisms (SNPs) in IBD5 using previous information of linkage disequilibrium extension reported in Japanese patients to determine whether there were variants in IBD5 specifically associated with IBD in Japanese patients. Material and methods. A total of 758 Japanese individuals, 241 patients with CD, 247 patients with ulcerative colitis (UC) and 270 healthy controls, were analyzed in this study. Genotyping for SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Results. We found L503F and −207G/C to be very rare (<1% frequency) in CD, UC and HC in the Japanese population. Furthermore, we also found that none of the representative SNPs in IBD5 was associated with CD or UC in the Japanese subjects. Conclusions. In contrast to Caucasians, IBD5 is not a major component of the susceptibility to IBD in the Japanese population.

Mapping of a disease susceptibility locus in chromosome 6p in Japanese patients with ulcerative colitis

Ulcerative colitis (UC) is a multifactorial disorder with both genetic and environmental factors. HLA-B*52 and DRB1*1502 are reported to be strongly associated with UC in Japan. However, the actual susceptible gene has not been identified yet. In this study, to map precisely the susceptible locus for UC, we performed association mapping in the chromosome 6p using 24 microsatellite markers distributed over 16 Mb. A total of 183 patients with UC and 186 healthy controls (HC) were included in this study. In all, 15 markers around the human leukocyte antigen (HLA) region showed statistical significance in the genotypic differentiation test concerned with the allelic distribution between the UC and HC. Especially, the markers between the centromeric region of HLA class I and the telomeric region of class III showed remarkably low P-values and the allele239 of C2-4-4 in class I marker showed the strongest association (Pc=2.9 × 10−9: OR=3.74, 95% CI=2.50–5.60). Furthermore, we found strong linkage disequilibrium (LD) between the allele239 of C2-4-4 and HLA-B*52 in haplotype analysis. These results provide evidence that, in Japanese, important determinants of disease susceptibility to UC may exist in HLA, especially between the centromeric region of class I and the telomeric region of class III, under the strong LD with HLA-B*52.

Rupture of rectal varices treated with endoscopic variceal ligation.

We report here 3 cases of rectal varices treated with endoscopic variceal ligation and discuss the pathogenesis, treatment, and prognosis of rectal varices with referring to previous reports. Of the 3 patients, 2 had been diagnosed as liver cirrhosis and 1 as extrahepatic portal hypertension. All of the 3 patients had previously undergone treatment of esophagogastric varices. The rupture of rectal varices appeared to have some relationship with the treatment of esophageal varices. In previous reports, 73% of patients with ruptured rectal varices treated with endoscopic injection sclerotherapy or endoscopic variceal ligation had undergone treatments of esophageal varices. The endoscopic treatments resulted in a favorable prognosis in 2 patients. Although no fatality from endoscopic injection sclerotherapy or endoscopic variceal ligation has been reported, 1 of the present 3 cases died of liver failure.

The T3b gene promoter directs intestinal epithelial cell-specific expression in transgenic mice

Although a few promoters that direct intestinal epithelial cell‐specific expression in transgenic animals have been reported, they are not necessarily appropriate for transgenic studies in terms of activity and tissue specificity. Here, we examined the tissue specificity of transgene expression directed by the 2.8‐kb promoter region of the T3b gene, which encodes one of the non‐classical major histocompatibility complex class I molecules. The transgene was expressed exclusively in the epithelial cells of the small and large intestines at high levels. The results indicate that the T3b promoter is useful for directing transgene expression specifically in intestinal epithelial cells.

Microsatellite instability and loss of heterozygosity in the nondysplastic colonic epithelium of ulcerative colitis.

Background. A major longterm risk for patients with ulcerative colitis (UC) is the development of colorectal dysplasia and cancer. Microsatellite instability (MI) has now been reported not only in colitic cancers but also in dysplasias, and even in nondysplastic inflamed mucosa. With the conventional microdissection technique, however, contamination by nonepithelial cells cannot be prevented and this could produce less reliable results than other methods. Therefore, we examined the condition of MI and loss of heterozygosity (LOH) of UC epithelium using a crypt isolation technique. Methods. One hundred and twenty-nine biopsy samples from 21 patients with UC were investigated for histology and microsatellite status, using nine microsatellite markers. A total of 1031 polymenase chain reaction (PCR) products were evaluated. Results. We found that no microsatellite markers displayed instability, but LOH at the 3p locus was detected in the nondysplastic epithelium of one patient with longstanding UC. Conclusions. Our study strongly suggests that MI does not contribute to the progression of the colitis-dysplasia sequence.