Genetic background of autoimmune hepatitis in Japan

Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Several studies from ethnically different countries have clarified that the genetic predisposition to type 1 AIH is linked mainly to human leukocyte antigen (HLA)-class II genes. Recently, molecular analysis using polymerase chain reaction (PCR)-based DNA typing has revealed that susceptibility to type 1 AIH is primarily associated with the HLA class II DRB1 locus, which encodes a polymorphic beta chain of the HLA-DR antigen. However, additional susceptibility genes (either HLA or non-HLA) and/or environmental factors may also contribute to the development of type 1 AIH; in Japanese type 1 AIH patients, although the most influential gene in disease susceptibility is HLA-DRB1*04:05, several other genes have been identified as being involved in AIH pathogenesis or resistance and are the currently the focus of single nucleotide polymorphism analysis.ArticleJOURNAL OF GASTROENTEROLOGY. 46(1):42-47 (2011)journal articl

Endoscopic Retrograde Cholangiopancreatography Using a Multi-bending Duodenoscope in Patients with a Billroth I Gastrectomy

Article信州医学雑誌 63(6):385-389(2015)journal articl

A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis

ArticleScientific reports.8 :11924(2018)journal articl

A2BP1 as a novel susceptible gene for primary biliary cirrhosis in Japanese patients

Primary biliary cirrhosis (PBC) is a complex autoimmune liver disease with an etiology that remains to be conclusively elucidated. As such, we screened the human genome for genes that might influence PBC susceptibility or resistance using 400 microsatellite markers. A strong candidate gene indicated by susceptibility microsatellite markers was further evaluated by association analysis using single nucleotide polymorphisms (SNPs). A total of 126 patients with PBC and 95 healthy Japanese controls were enrolled. Four candidate susceptible regions and seven candidate protective regions were statistically associated with PBC. Because the D16S423 marker on chromosome 16p showed the strongest evidence of linkage, the protein-coding gene ataxin 2-binding protein 1 (A2BP1) lying 27 kb on the centromeric side of D16S423 was targeted as a candidate susceptible gene. Seven SNPs (rs17139207, rs12926282, rs17139244, rs6500742, rs4146812, rs4124065, and rs889699) in the A2BP1 gene were genotyped in patients and controls. The rs17139244 SNP was found to be weakly associated with PBC in an additive model. The genotype frequency of the major C allele at rs6500742 was significantly associated with PBC, compared with healthy controls. This study showed a total of 11 candidate PBC susceptibility or resistance regions. In particular, the A2BP1 gene might play a pivotal role for susceptibility to PBC.ArticleHUMAN IMMUNOLOGY. 71(5):520-524 (2010)journal articl

Comparison of Hepatitis B Virus DNA, RNA, and Core Related Antigen as Predictors of Lamivudine Resistance in Patients with Chronic Hepatitis B

The clinical usefulness of hepatitis B virus (HBV)DNA, RNA, and core related antigen (HBcrAg)assays for predicting the appearance of HBV DNA breakthrough was evaluated and compared in patients with chronic hepatitis B undergoing lamivudine therapy.Methods :Thirty six patients with chronic hepatitis B who received lamivudine therapy for more than 1 year were enrolled. HBV RNA was measured simultaneously with HBV DNA (HBV RNA/DNA) using a real-time detection polymerase chain reaction assay with a preceding step of reverse-transcription. HBV DNA was measured by an HBV AMPLICOR monitor kit. HBcrAg was measured using a chemiluminescence enzyme immunoassay. Results : Sixteen patients (44%) developed HBV DNA breakthrough during the median observation period of 48.4 months (range 7.4-87.8 months). Afterwards, HBV DNA breakthrough was prospected using the three parameters taken 6 months after starting lamivudine therapy. The cut-offlevels for predictions were determined by receiver operating characteristic curves, and were 2.6 log copies/ml for HBV DNA, 3.8 log U/ml for HBV RNA/DNA, and 4.0 log U/ml for HBcrAg.Sensitivity,specificity,and accuracy for predicting HBV DNA breakthrough were 25%, 100%,and 67% respectively for HBV DNA.Similarly,they were 50%,90%,and 72% for HBV RNA/DNA, and 100%, 40%, and 67% for HBcrAg. Conclusion : Our findings confirm that HBV DNA is useful for identifying patients who are at high risk for HBV breakthrough.HBcrAg is useful for isolating those who are at low risk, and HBV RNA/DNA showed predictive characteristics similar to HBV DNA with higher sensitivity and the highest accuracyArticle信州医学雑誌, 58(4):153-162 (2010)departmental bulletin pape

Genetic Contribution to the Pathogenesis of Primary Biliary Cholangitis

Formerly termed primary biliary cirrhosis, primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease characterized by the presence of antimitochondrial antibodies. Ursodeoxycholic acid (UDCA) therapy is the most effective and approved treatment for PBC and leads to a favorable outcome in the vast majority of cases. Although the etiology of PBC has not yet been elucidated, human leukocyte antigen (HLA) class II alleles have been consistently associated with disease onset for decades. Individuals in different geographic regions of the world may have varying susceptibility alleles that reflect indigenous triggering antigens. In this review, we describe the influence of HLA alleles and other gene polymorphisms on PBC along with the results of genome-wide association studies (GWAS) on this disease

Association of Autoimmune Hepatitis with Src homology 2 adaptor protein 3 Gene Polymorphisms in Japanese Patients

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio [OR] = 0.68; corrected P = 0.025). Haplotype 2 (rs2238154 A, rs11065904 T, and rs739496 G) was associated with resistance to AIH (OR 0.67, P = 0.021) as well as to autoimmune pancreatitis (OR = 0.70, P = 0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.ArticleJournal of Human genetics. 62: 963-967. (2017)journal articl

A Case of Esophageal Hemangioma Successfully Treated by Endoscopic Injection Sclerotherapy

Article信州医学雑誌 64(2): 75-78(2016)journal articl

Human leukocyte antigen class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis

Along with twin and family studies, recent genome-wide association studies suggest that genetic factors contribute to the susceptibility and severity of primary biliary cirrhosis (PBC). Although several reports have demonstrated that the human leukocyte antigen (HLA) DRB1*08:03 allele is associated with disease susceptibility in Japan, the precise analysis of HLA haplotypes and the role of amino acid alignment have not been fully clarified. We investigated HLA class I A, B, and C and HLA class II DRB1 and DQB1 alleles and haplotypes in 229 Japanese patients with PBC and compared them with the published data of 523 healthy subjects. Significant associations were found with PBC susceptibility for the DRB1*08:03-DQB1*06:01 (13% versus 6%; P = 0.000025; odds ratio [OR] = 2.22) and DRB1*04:05-DQB1*04:01 haplotypes (17% versus 13%; P = 0.044; OR = 1.38). Conversely, there were significant protective associations with the DRB1*13:02-DQB1*06:04 (2% versus 5%; P = 0.00093; OR = 0.27) and DRB1*11:01-DQB1*03:01 haplotypes (1% versus 4%; P = 0.03; OR = 0.37). The frequency of the DRB1*09:01-DQB1*03:03 haplotype was significantly higher in patients who had received orthotopic liver transplantation (33% versus 11%; P = 0.0012; OR = 3.96). Furthermore, the frequency of serine at position 57 (P = 0.0000015; OR = 1.83) of the DR beta chain differed the most in patients with PBC, compared with healthy subjects. Conclusion: This study established the role of HLA haplotypes in determining PBC susceptibility and progression in the Japanese population. Further resequencing of the HLA region is required to more precisely identify the genetic components of PBC. (HEPATOLOGY 2012)ArticleHEPATOLOGY. 55(2):506-511 (2012)journal articl

Association between KIR-HLA combination and ulcerative colitis and Crohn's disease in a Japanese population

ArticlePloS One. 13(4) :e0195778(2018)journal articl