Fine mapping identifies independent HLA associations in autoimmune hepatitis type 1

Abstract

Background & aims: Association studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.

Methods: We performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.

Results: A total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10^-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10^-33; OR = 4.26) and rs7765379 (p = 5.08 × 10^-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.

Conclusions: Our study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.

Impact and implications: This study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

Keywords: Autoimmune hepatitis; HLA-B∗35:01; Human leucocyte antigen.

Graphical abstract

Fig. 1

Overview of genetic effects in the MHC region influencing risk for AIH. The analysis was conducted using logistic regression models. The horizontal axis shows genomic position and the vertical axis shows negative log10-transformed p values for association. The horizontal dashed line corresponds to the significance threshold of p = 5 × 10⁻⁸. The colour of the circles indicates the type of the marker: grey, SNPs; blue, amino acids; and red, classical HLA alleles. AIH, autoimmune hepatitis; HLA, human leucocyte antigen; MHC, major histocompatibility complex; SNP, single nucleotide polymorphism.

Fig. 2

Transethnic meta-analysis of the effects of the reported HLA alleles. Forest plot shows the estimated odds ratio (OR) with 95% CI of each cohort. The relative weight of each study in the meta-analysis is represented by the size of the squares. The solid black line represents OR = 1 and the red dashed line indicates OR from the fixed-effect meta-analysis.

Fig. 3

Stepwise logistic regression of the variants for AIH in the MHC region. (A) Conditioned on HLA-B∗35:01, (B) conditioned on HLA-B∗35:01 and HLA-B∗08:01, (C) conditioned on HLA-B∗35:01, HLA-B∗08:01 and rs7765379, (D) conditioned on HLA-B∗35:01, HLA-B∗08:01, rs7765379, and HLA-DRB1-73G. The analysis was conducted using logistic regression models. For each plot, the horizontal axis shows genomic position and the vertical axis shows negative log10-transformed p values for association. The horizontal dashed line corresponds to the significance threshold of p = 5 × 10⁻⁸. The colour of the circles indicates the type of the marker: grey, SNPs; blue, amino acids; and red, classical HLA alleles. HLA, human leucocyte antigen; SNP, single nucleotide polymorphism.

Fig. 4

Summary of association results between HLA variants and clinical phenotypes in the AIH cohort. The analysis was conducted using linear regression models. Plots of the association between HLA variants with serum levels of AST (A), ALT (B) and IgG (C). For each plot, the horizontal axis shows genomic position and the vertical axis shows negative log10-transformed p values for association. The horizontal dashed line corresponds to the significance threshold of p = 5 × 10⁻⁸. The colour of the circles indicates the type of the marker: grey, SNPs; blue, amino acids; and red, classical HLA alleles. AIH, autoimmune hepatitis; ALT, alanine transaminase; AST, aspartate transaminase; HLA, human leucocyte antigen; IgG, immunoglobulin G; SNP, single nucleotide polymorphism.