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Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis

Lammert, C., McKinnon, E.J., Chalasani, N. and Phillips, E.J. (2019) Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis. Clinical and Translational Gastroenterology, 10 (6).

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HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist.

We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01.

DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P = 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P = 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles.

Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.

Item Type: Journal Article
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Wolters Kluwer
Copyright: © 2019 The Author(s).
United Nations SDGs: Goal 3: Good Health and Well-Being
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