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

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

ArticleScientific reports.8 :11924(2018)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

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

Formation of Crosslinked Polyurea Membrane by Phase Separation Method

This research was conducted to clarify the membrane formation mechanism of crosslinked polyurea microcapsules by phase separation method, specially the role of polymeric surfactant of poly(ethylene-alt-maleic anhydride),(poly(E-MA))at the interface of O/W emulsion. Because of its toxicity, alternative chemicals should be chosen. This understanding may make possible to find the alternative chemicals. It was found that poly(E-MA)was necessary for the formation of crosslinked polyurea membrane. The addition of sodium dodecyl sulfate (SDS) prohibited the membrane formation reaction at the interface, even in the care of poly(E-MA) concentration enough for polymeric microcapsule formation. From the results in this study, poly(E-MA) as polymeric surfactant was found to be adsorbed on the interface of O/W emulsion and provide the reaction site for the membrane formation of polymeric microcapsules

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

Association analysis of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with primary biliary cirrhosis in Japanese patients

Background & Aims: Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease of still unidentified genetic etiology that is characterized by chronic inflammation of the liver. Since cytotoxic T-lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with PBC susceptibility in studies on Caucasians, we investigated the genetic association between CTLA4 polymorphisms and PBC in a Japanese population. Methods: Five single nucleotide polymorphisms (SNPs) in the CTLA4 gene (rs733618, rs5742909, rs231775, rs3087243, and rs231725) were genotyped in 308 patients with PBC and 268 healthy controls using a TaqMan assay. Results: One CTLA4 gene SNP (rs231725) was significantly associated with susceptibility to anti-mitochondrial antibody (AMA)-positive PBC, but clinical significance disappeared after correction for multiple testing. Moreover, CTLA4 gene SNPs did not influence AMA development or disease progression to orthotopic liver transplantation in our Japanese cohort. In haplotype analyses, one haplotype [haplotype 1 (CGGA)] at rs5742909, rs231775, rs3087243, and rs231725, was significantly associated with susceptibility to both AMA-positive PBC and overall PBC. Conclusions: This study showed that CTLA4 gene polymorphisms had a modest, but significant association with susceptibility to PBC in the Japanese population. The connection between genetic variants and the function of the CTLA4 gene remains to be addressed in future investigations.ArticleJOURNAL OF HEPATOLOGY. 53(3):537-541 (2010)journal articl

Serum interleukin (IL)-10 and IL-12 levels and IL28B gene polymorphisms: pretreatment prediction of treatment failure in chronic hepatitis C

Background: Both IL28B gene polymorphisms and serum levels of interleukin (IL)-10, IL-12p40 and IL-18 have been reported to affect the outcome of natural and pegylated interferon and ribavirin-treated HCV infection. Methods: To clarify their association and predictive value in treatment outcome of genotype 1 HCV-infected patients, we measured pretreatment serum IL-10, IL-12p40 and IL-18 levels using multiplex assays and determined IL28B gene polymorphisms (rs 8099917) in 52 cases with chronic hepatitis C. Results: High baseline levels of IL-10 (P<0.001) and low levels of IL-12p40 (P<0.001) were significantly associated with a non-virological response (NVR) in our cohort. The IL28B polymorphism was tested and TT, TG or GG genotypes were found in 60%, 38% and 2% of patients, respectively, with corresponding NVR rates of 10%, 60% and 100% (P<0.001). Serum cytokine levels were significantly correlated with IL28B gene polymorphisms. When serum IL-10 levels were stratified at 5.0 pg/ml, NVR rates were 50% versus 0% (P=0.004) for the IT genotype and 87% versus 0% (P=0.001) for the TG or GG genotypes. Similarly, low IL-12p40 levels were associated with an NVR in patients with TG or GG genotypes (P=0.006). In multivariate analysis, high IL-10, low IL-12p40 and IL28B TG or GG genotypes were independently associated with an NVR. Conclusions: Serum IL-10 and IL-12p40 levels in combination with IL28B genotype, especially G-allele carriage, are strong predictive markers of an NVR to HCV treatment with pegylated interferon and ribavirin.ArticleANTIVIRAL THERAPY. 16(7):1073-1080 (2011)journal articl

Serum chemokine levels are associated with the outcome of pegylated interferon and ribavirin therapy in patients with chronic hepatitis C

Aim: Serum chemokine levels and amino acid substitutions in the interferon-sensitivity determining region (ISDR) and core region have been associated with treatment outcome of pegylated interferon and ribavirin therapy in genotype 1 hepatitis C virus (HCV)-infected patients. The present study was conducted to clarify the association between serum chemokines and treatment outcome in patients with chronic HCV-1 infection in a Japanese cohort. Methods: A total of six serum chemokines were quantified before, during and after pegylated interferon and ribavirin treatment in 79 genotype 1 chronic HCV patients using a multiple bead array system. Viral ISDR and core region variants were determined by direct sequencing. Results: The baseline serum levels of eotaxin, IP-10 and RANTES were significantly higher in chronic HCV patients than in controls. High levels of eotaxin and macrophage inflammatory protein (MIP)-1 beta before therapy and more than two mutations in the ISDR were associated with a sustained virological response, and patients with more than two mutations in the ISDR also had significantly higher MIP-1 beta levels. Receiver-operator curve analysis showed a 77% sensitivity and 73% specificity for predicting an SVR using MIP-1 beta values. Conclusion: Serum MIP-1 beta levels may predict the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR.ArticleHEPATOLOGY RESEARCH. 41(6):587-593 (2011)journal articl

Association of Serum Cytokine Levels With Treatment Response to Pegylated Interferon and Ribavirin Therapy in Genotype 1 Chronic Hepatitis C Patients

Methods. We quantified a total of 8 serum cytokines before, during, and after treatment in 79 genotype 1 chronic HCV patients. Viral ISDR and core region variants were determined by direct sequencing. Results. High levels of interleukin (IL)-12 and IL-18 and more than 2 mutations in the ISDR were associated with a sustained virological response (SVR). Conversely, high baseline IL-10 levels and glutamine at amino acid 70 of the HCV core protein (Gln70) were significantly associated with a nonresponse to treatment, and patients with Gln70 had significantly higher IL-10 levels. In multivariate analysis, low IL-10, high IL-12, and high IL-18 levels were independently associated with an SVR. These 3 cytokine levels were decreased from baseline levels 4 weeks into treatment and remained low in patients with an SVR. Conclusion. Serum IL-10, IL-12, and IL-18 levels are predictive of the response to HCV treatment with pegylated interferon and ribavirin and are associated with amino acid substitutions in the ISDR and core region.ArticleJOURNAL OF INFECTIOUS DISEASES. 203(8):1087-1095 (2011)journal articl