HLA-C genes and susceptibility to type 1 autoimmune hepatitis.

Susceptibility to autoimmune hepatitis (AIH) is associated with the HLA A1-B8-DR3 haplotype, DR4 antigen, and, more specifically, the HLA DRB3*0101, DRB1*0301, and DRB1*0401 alleles. Few investigators, however, have examined the HLA C locus in AIH, which warrants detailed study in view of its recently described roles in immunoregulation. Eighty-seven adult, white patients with well-characterized type 1 AIH and 100 controls were studied. HLA C and HLA DRB1 alleles were assigned by polymerase chain reaction (PCR)-based genotyping. HLA A and B antigens were determined by standard microlymphocytotoxicity assay. Extended haplotypes were constructed according to known patterns of linkage disequilibrium. Only one HLA C locus allele, Cw*0701, which was present in 54% of patients versus 34% of controls (P = .006; relative risk [RR] = 1.54) was associated with AIH. The overall increase in the frequency of the Cw*07 gene (70.1% of patients vs. 54% of controls; P = .024; RR = 1.3) was due entirely to inheritance of the Cw*0701 allele rather than the other Cw*07 alleles, Cw*0702, *0703, and *0704. The RR for Cw*0701 (RR = 1.54) is greater than that for HLA A1 (RR = 1.33) and DRB1*0301 (RR = 1.49), but less than that for HLA-B8 (RR = 1.75). The present findings suggest that the gene or genes conferring susceptibility to AIH lie in the region centromeric to the HLA A locus between HLA C and DRB1. Although linkage disequilibrium with both B8 and DRB1*0301 may account for our finding of an increased frequency of Cw*0701, it is also possible that this allele contributes to disease susceptibility, perhaps by interaction with natural killer cells or cytotoxic T lymphocytes.

Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis.

BACKGROUND & AIMS: In a recent study, we suggested that susceptibility to type 1 autoimmune hepatitis is associated with a six-amino acid motif, LLEQKR, within the DR beta polypeptide, but these data are in conflict with contemporary reports from Japan and Argentina. The purpose of the present study was to reexamine this question in a large independent cohort of patients. METHODS: Eighty-six North American white patients and 102 control subjects were studied. HLA class I antigens were determined serologically, and the DRB1, DQA1, DQB1, and DPB1 genes and the DRB3/4/5 subtypes were determined by high-resolution genotyping. RESULTS: The greatest risk was associated with DRB1*0301 (corrected probability [Pc] = 0.00003; relative risk [RR] = 4.58), and a secondary association with DRB1*0401 was identified (Pc = 0.000132; RR = 5.97). Protection from disease was associated with the DRB5*0101-DRB1*1501 haplotype (Pc = 0.021; RR = 0.3). However, further analysis indicated that a lysine residue at position 71 of the DR beta polypeptide may be the most important determinant of disease susceptibility (P = 0.0000003; RR = 8.6, increasing to RR = 16.38 with four lysine residues). CONCLUSIONS: DRB1*0301 and DRB1*0401 are confirmed as the principal susceptibility alleles for type 1 autoimmune hepatitis, and these data support the hypothesis that a lysine residue at position 71 of the DR beta-polypeptide chain may be the major risk factor.

Associations between alleles of the major histocompatibility complex and type 1 autoimmune hepatitis.

Susceptibility for type 1 autoimmune hepatitis has been associated with the major histocompatibility alleles DRB1*0301, DRB3*0101, DRB1*0401, and DRB4*0103, whereas the DRB1*1501 allele may protect from the disease. Our aim was to determine if these alleles or others influence clinical manifestations and prognosis. Eighty-six white patients were evaluated prospectively for immune features and outcomes. Class I alleles were determined by microlymphocytotoxicity, and class II alleles were assessed by polymerase chain reaction with sequence-specific oligonucleotide probes or sequence-specific primers. One hundred two white, normal subjects were typed in the same fashion. Patients with concurrent immunologic diseases were more commonly positive for DRB4*0103 than patients without these features (68% vs. 38%, P = .01). DRB1*0301 (86% vs. 45%, P = .008) and the DRB1*0301-DRB3*0101 haplotype (79% vs. 42%, P = .02) occurred more commonly in patients who deteriorated during corticosteroid therapy. In contrast, DRB1*0401 and the DRB1*0401-DRB4*0103 haplotype were associated with a lower frequency of death from liver failure or the need for transplantation than patients with other alleles (0% vs. 37%, P = .03). Patients with DRB1*0301 differed from those with DRB1*0401 in that they were younger and failed treatment more commonly (27% vs. 5%, P = .04). We conclude that alleles associated with susceptibility to type 1 autoimmune hepatitis also influence its clinical features and prognosis. DRB4*0103 is associated with concurrent immune diseases, DRB1*0301 with a poor treatment response, and DRB1*0401 with a lower frequency of hepatic death or transplantation.