Human Leukocyte Antigen Profile Predicts Severity of Autoimmune Liver Disease in Children of European Ancestry.

Abstract

Genetic predisposition to autoimmune hepatitis (AIH) in adults is associatedwith possession of human leukocyte antigen (HLA) class I (A*01,B*08) and class II (DRB1*03,-04, -07, or-13) alleles,depending on geographic region. Juvenile autoimmune liver disease (AILD) comprises AIH-1, AIH-2, and autoimmune sclerosing cholangitis (ASC), which are phenotypically different from their adult counterparts. We aimed to define the relationship between HLA profile and disease course, severity, and outcome in juvenile AILD. We studied 236 children of European ancestry (152 female [64%], median age 11.15 years, range 0.8-17), including 100 with AIH-1, 59 with AIH-2, and 77 with ASC. The follow-up period was from 1977 to June 2019 (median 14.5 years). Class I and II HLA genotyping was performed using PCR/sequence-specific primers.HLAB*08, -DRB1*03, and theA1-B8-DR3haplotype impart predisposition to all three forms of AILD. Homozygosity forDRB1*03represented the strongest risk factor (8.8). HLADRB1*04,which independently confers susceptibility to AIH in adults, was infrequent in AIH-1 and ASC, suggesting protection; and DRB1*15 (DR15)was protective against all forms of AILD. Distinct HLA class II alleles predispose to the different subgroups of juvenile AILD:DRB1*03to AIH-1,DRB1*13to ASC, andDRB1*07to AIH-2. Possession of homozygousDRB1*03 or of DRB1*13 isassociated with fibrosis at disease onset, and possession of these two genes in addition toDRB1*07is associated with a more severe disease in all three subgroups. Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predictingresponsiveness to immunosuppressive treatment and course.