AUTHOR=Khor Seik-Soon , Ueno Kazuko , Nishida Nao , Kawashima Minae , Kawai Yosuke , Aiba Yoshihiro , Hitomi Yuki , Nagasaki Masao , Nakamura Minoru , Tokunaga Katsushi 

TITLE=Novel HLA allele associations with susceptibility, staging, symptomatic state, autoimmune hepatitis and hepatocellular carcinoma events for primary biliary cholangitis in the Japanese population

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1151502

DOI=10.3389/fimmu.2023.1151502

ISSN=1664-3224

ABSTRACT=<p>Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen <italic>(HLA)-DR/DQ</italic>-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution <italic>HLA</italic> imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific <italic>HLA</italic> reference panels. Eighteen previously reported Japanese PBC-associated <italic>HLA</italic> alleles were confirmed and extended to 3-field-resolution, including <italic>HLA-DRB1*08:03</italic> to <italic>HLA-DRB1*08:03:02</italic>, <italic>HLA-DQB1*03:01</italic> to <italic>HLA-DQB1*03:01:01</italic>, <italic>HLA-DQB1*04:01</italic> to <italic>HLA-DQB1*04:01:01</italic> and <italic>HLA-DQB1*06:04</italic> to <italic>HLA-DQB1*06:04:01</italic>. In addition, additional significant novel <italic>HLA</italic> alleles were identified, including 3 novel susceptible <italic>HLA-DQA1</italic> alleles: <italic>HLA-DQA1*03:03:01</italic>, <italic>HLA-DQA1*04:01:01</italic>, <italic>HLA-DQA1*01:04:01</italic> and 1 novel protective <italic>HLA-DQA1</italic> allele, <italic>HLA-DQA1*05:05:01</italic>. In addition, PBC patients carrying <italic>HLA-DRB1*15:01:01</italic> and <italic>HLA-DQA1*03:03:01</italic> would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible <italic>HLA</italic> alleles of <italic>HLA-A*26:01:01</italic>, <italic>HLA-DRB1*09:01:02</italic> and <italic>HLA-DQB1*03:03:02</italic>. Lastly, <italic>HLA-DPB1*05:01:01</italic> was identified as a potential risk <italic>HLA</italic> allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of <italic>HLA</italic> allele associations to 3-field resolution and identified novel <italic>HLA</italic> allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.</p>