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

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

ArticleScientific reports.8 :11924(2018)journal articl

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

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

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