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

Abstract

Background and aims: Genetic predisposition to autoimmune hepatitis (AIH) in adults is associated with 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.

Approach and results: 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. HLA B*08, -DRB1*03, and the A1-B8-DR3 haplotype impart predisposition to all three forms of AILD. Homozygosity for DRB1*03 represented the strongest risk factor (8.8). HLA DRB1*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*03 to AIH-1, DRB1*13 to ASC, and DRB1*07 to AIH-2. Possession of homozygous DRB1*03 or of DRB1*13 is associated with fibrosis at disease onset, and possession of these two genes in addition to DRB1*07 is associated with a more severe disease in all three subgroups.

Conclusions: Unique HLA profiles are seen in each subgroup of juvenile AILD. HLA genotype might be useful in predicting responsiveness to immunosuppressive treatment and course.

Figure 1.. Transplant-free survival curves of AILD children with different HLA genotypes.

The association of HLA DRB1* genotypes and transplant-free survival was calculated by Kaplan-Meier survival plot. X axis: the year of survival, defined as the years from diagnosis until the time of liver transplant or death, cut off at year 20; Y axis: percentage of survival. Panel A: Overall survival in the different subgroups of AILD independently from HLA genotype. The survival rate in AIH-1 tended to be higher than in AIH-2 (p=0.06). Panels B to E: Survival according to HLA DRB1* genotypes in AIH-1, AIH-2 and ASC respectively. No significant difference in survival was observed among subgroup of AILD patients.

Figure 2.. Frequencies of HLA class I and class II alleles, and haplotypes in 236 patients with autoimmune liver disease and 209 healthy controls.

Light dotted bar = AIH-1; dark dotted bar = ASC; diagonal stripe bar = AIH-2; grey bar = healthy controls. * : P<0.05; ** : P≤0.001 compared to healthy controls.