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

Abstract

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

Keywords: HLA; Scheuer staging system; autoimmune hepatitis; hepatocellular carcinoma; primary biliary cholangitis.

Figure 1

(A) Schematic representation of HLA allele resolutions in relation to the mutation sites on the HLA class I and II genes. The 2-field resolution covers the changes in amino acid sequences of the encoded protein for HLA alleles while the 3-field resolution of HLA alleles takes into account changes in all exons that differ by synonymous nucleotide substitutions. Finally, the 4-field resolution encompasses differences in sequence polymorphism in the 5’ or 3’ untranslated regions and introns. α1/2/3, alpha chain; β1, beta chain; β2m, beta2 microglobulin; TM, transmembrane region; CYT, cytoplasmic tail. (B) Schematic representation of the study design. 3-field HLA imputation were performed using the SNP genotyping data from GWAS of Japanese PBC. HLA alleles association test were carried out by stratifying based on susceptibility, staging (Scheuer), symptomatic, PBC with AIH and PBC with HCC.

Figure 2

HLA allele linkage distributions of HLA-A, -C, -B, -DRB1, -DQA1, -DQB1, and -DPB1 in Japanese PBC. The heights of the bars show the number of samples carrying the particular HLA alleles, and grey lines connecting orange bars indicate the proportion of linkage between different orange bars. Susceptible and protective HLA haplotypes are highlighted in magenta and yellow, respectively.