1 Although

twin and family studies suggest that genetic f

1 Although

twin and family studies suggest that genetic factors contribute to disease susceptibility and severity,2, 3 the cause of PBC remains poorly understood.4 Significant associations of genetic factors, including HLA alleles, tumor necrosis factor alpha,5–8 and cytotoxic T-lymphocyte AUY-922 antigen 4,8–14 with PBC have been reported. Among these, only HLA has consistently been associated with PBC susceptibility.15 The HLA-DRB1*08 family of alleles has been the most frequently described determinant for susceptibility to PBC16–21; HLA-DRB1*08:03 has been associated with PBC in the Japanese.22–26 However, HLA DQB1 alleles and haplotypes have not been fully investigated, and large cohort studies have indicated that HLA-DRB1*11 and DRB1*13 alleles are, in fact, protective against PBC.20, 21, 26 Because recent genome-wide studies of PBC have shown the strongest association signals in the HLA region,27–30 we sought to determine whether particular HLA alleles or haplotypes or DRB1 allele amino acid alignments were associated with susceptibility

to PBC or disease progression in the Japanese population. CI, confidence interval; HLA, human leukocyte antigen; OLT, orthotopic liver transplantation; OR, odds ratio; PBC, primary biliary cirrhosis. Clinical and biochemical features of 229 PBC patients who were enrolled for this study between January 2005 and September 2010 are shown in Table 1. The racial background of all patients was Japanese. HLA class I and II allelic genotypes from 523 healthy subjects obtained in a previous learn more study were available as controls.31 In addition, HLA class II allelic genotypes from 130 patients with chronic hepatitis C virus infection were adopted from another study as comparison cases having another liver disease.32 The diagnosis of PBC was based on criteria from the American Association for the Study of Liver Diseases.33 Serum antimitochondrial antibody was determined using indirect immunofluorescence, and a titer of ≥1:40 was considered to be positive.34 Our serological protocol did not include testing for particular antinuclear antibodies, such as IMP dehydrogenase ani-gp210 antibody reactivity, or antimitochondrial antibody titration. All patients

were negative for hepatitis B surface antigen, antibody to hepatitis B core antigen, antibody to hepatitis C virus, and antibody to human immunodeficiency virus. Patients were classified into two stages of PBC, based on their most recent follow-up: Early-stage patients were histologically Scheuer stage I or II35 or of unknown histological stage without liver cirrhosis, and late-stage patients were histologically Scheuer stage III or IV or clinically diagnosed with liver cirrhosis or hepatic failure.14 Liver cirrhosis was diagnosed by histological examination and/or characteristic clinical signs of advanced liver disease.36 All subjects provided written informed consent for this study, which was approved by the institutional ethics committee.

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