||The efficacy of treatment of Th differentiation in active Crohn’s disease.
||Gastrointestinal findings of Birt-Hogg-Dube syndrome.
||Junji Umeno, Yuta Fuyuno, Takehiro Torisu, Atsushi Hirano, Motohiro Esaki, Shunichi Yanai, Naoki Ohmiya, Tadakazu Hisamatsu, Kenji Watanabe, Naoki Hosoe, Haruhiko Ogata, Fumihito Hirai, Takashi Hisabe, Toshiyuki Matsui, Tsuneyoshi Yao, Takanari Kitazono, Takayuki Matsumoto; CEAS study group, A nationwide survey of chronic enteropathy associated with SLCO2A1 gene in Japan, The 15th Congress of European Crohn's and Colitis Organization (ECCO 2020), 2020.02, Background: Chronic enteropathy associated with SLCO2A1 gene (CEAS) is an autosomal recessive disease caused by mutations in the SLCO2A1 gene which encodes a prostaglandin transporter. It is a rare intractable disease characterized by persistent blood and protein loss due to the small intestinal ulcers. Because CEAS mimics Crohn's disease (CD) concerning ileal ulcers and stenoses, it is often difficult to distinguish CEAS from CD based on gastrointestinal findings alone. Furthermore, SLCO2A1 gene mutations are also known to cause primary hypertrophic osteoarthropathy (PHO) and some CEAS patients manifest digital clubbing, periostosis, acroosteolysis, and thickened skin as extra-intestinal manifestations. Since little is known about the clinical features of CEAS, we conducted a nationwide survey in Japan.
Methods: All study participants provided written informed consent for genetic analysis. The present study was approved by the ethics committee of each institution. During the period between 2012 and 2019, 141 patients suspected of CEAS were enrolled in this study and checked to have SLCO2A1 gene mutations. We reviewed the clinical information of genetically confirmed CEAS patients.
Results: We confirmed 61 CEAS patients (21 males and 40 females) and found 14 different types of recessive SLCO2A1 mutations. The median age at disease onset and diagnosis was 18.5 (range 1-69) and 40 (range 7-70) years, respectively. Parental consanguinity was present in 16 patients (26%). Although anaemia was present in almost all patients, only two patients experienced gross haematochezia. The median haemoglobin and serum protein levels at diagnosis were 9.7 (range 2.3-13.7) and 5.2 (2.7-8.2) g/dl, respectively. Thirty-three patients (54%) had undergone intestinal surgery. They showed relatively low inflammatory markers in blood tests (median CRP, 2.9 mg/l). The most frequently involved gastrointestinal site was ileum (93%), but the terminal ileum was rarely involved (Figure). Mild digital clubbing or periostosis was found in 16 patients (26%), with six male patients fulfilling the major diagnostic criteria of PHO. The major manifestations of PHO were more frequently found in males than in females (digital clubbing 57% vs 10%; periostosis 52% vs 11%; pachydermia 62% vs 0%).
Conclusion: Although CEAS frequently causes intestinal strictures like CD, its clinical features seem to be distinct from those of CD. Also, a gender difference in clinical symptoms needs to be considered, because concurrent PHO can be frequently seen especially in male patients with CEAS..
||梅野 淳嗣, 江﨑 幹宏, 平野 敦士, Clinical features of chronic enteropathy associated with SLCO2A1 gene (CEAS), 12th Congress of European Crohn's and Colitis Organisation, 2017.02.
||梅野 淳嗣, Chronic enteropathy associated with SLCO2A1 gene, encoding prostaglandin transporter (CEAS): relationship with primary hypertrophic osteoarthropathy. , The 4th Annual Meeting of AOCC, 2016.07.
||Junji Umeno, Tadakazu Hisamatsu, Motohiro Esaki, Atsushi Hirano, Takayuki Matsumoto, Chronic enteropathy associated with SLCO2A1 gene, encoding prostaglandin transporter (CEAS), 2015 Advances in Inflammatory Bowel Diseases: Crohn's & Colitis Foundation of America's Clinical & Research Conference, 2015.12.
||平野 敦士, 梅野 淳嗣, 浅野 光一, 江﨑 幹宏, 松本 主之, A functional variant of SLC26A3 in association with ulcerative colitis down regulates SLC26A3 expression, 10th Congress of European Crohn´s and Colitis Organisation, 2015.02, Background
Our recent genome-wide association study has identified that rs2108225, located at 9 kb upstream of SLC26A3 gene, is associated with the susceptibility to ulcerative colitis (UC) in a Japanese population. The present study aimed to identify a functional variant in this locus.
We first carried out a re-sequencing of this locus using 94 UC cases to determine other misidentified causal variants. After fine-mapping, we investigated possible association of the identified single nucleotide polymorphisms (SNPs) and UC by single-marker and haplotype analyses using 752 UC cases and 2068 controls. Allelic difference in binding affinity to nuclear proteins of each SNP was evaluated by electrophoretic mobility shift assay (EMSA) and luciferase reporter assay. We also performed a chromatin immunoprecipitation (ChIP) assay to analyze the difference in binding affinity to the specific transcription factor.
We identified 24 newly identified SNPs by re-sequencing and genotyped a total of 99 SNPs in this locus. The strongest signal was observed at rs6466189 (P = 7.51 × 10-6), which was absolutely linked with rs2108225 and other seven SNPs (r2>0.95, respectively), in single-marker analysis. Haplotype analysis failed to identify any haplotype showing stronger association with UC than the nine SNPs. EMSA and reporter assay showed different binding affinity to nuclear proteins in rs7785790, causing the difference in transcriptional activity. In ChIP assay, such a difference in transcription relative to rs7785790 was caused by the negative transcription factor YY1, which suppressed the transcriptional activity by binding to the susceptible A allele.
The present study suggests that the functional variant rs7785790 affects the transcription of SLC26A3 by altering the binding affinity to YY1. Lower expression of SLC26A3 in the colonic mucosa might be associated with the susceptibility to UC..
||Umeno Junji, A functional variant of SLC26A3 in association with ulcerative colitis down regulates SLC26A3 expression, The 1st Annual Meeting of AOCC, 2013.06.
||UMENO JUNJI, Asano Kouichi, Takayuki Matsumoto, Takanari Kitazono, Replication of susceptibility loci identified by genome-wide association studies for ulcerative colitis in Japanese population., 7th Congress of the European Crohn's and Colitis Organisation, 2012.02.