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with other HLA alleles. 4,5,7,8 Furthermore, patients with HLA Susceptibility for type 1 autoimmune hepatitis has DR3 present at an earlier age and enter remission less frebeen associated with the major histocompatibility quently during corticosteroid therapy. 4,6,7 They also relapse alleles DRB1*0301, DRB3*0101, DRB1*0401, and after corticosteroid withdrawal, deteriorate during therapy, DRB4*0103, whereas the DRB1*1501 allele may protect and require liver transplantation more often than patients from the disease. Our aim was to determine if these alwith HLA DR4. 6-10 Because the alleles encompassing DR3 leles or others influence clinical manifestations and and DR4 encode specific amino acid sequences in the DRb prognosis. Eighty-six white patients were evaluated propolypeptide that determine the ability of each class II molespectively for immune features and outcomes. Class I cule to bind and present antigens to T cells, they can directly alleles were determined by microlymphocytotoxicity, influence the immunoreactivities of the effector cells responand class II alleles were assessed by polymerase chain reaction with sequence-specific oligonucleotide probes sible for the disease and, in turn, its clinical expression. 7 or sequence-specific primers. One hundred two white, Current nomenclature of the World Health Organization normal subjects were typed in the same fashion. Patients describes the specific HLA alleles rather than antigens. In with concurrent immunologic diseases were more com-this system, the genetic locus is first identified (i.e., DRB1), monly positive for DRB4*0103 than patients without followed by an asterisk and a four-figure code. The first two these features (68% vs. 38%, P Å .01). DRB1*0301 (86% vs. numbers of the code represent the old allelic group that often 45%, P Å .008) and the DRB1*0301-DRB3*0101 haplotype is equivalent to the serologically defined antigen. Thus, in (79% vs. 42%, P Å .02) occurred more commonly in pa-DRB1*04, the 04 represents DR4. The last two numbers refer tients who deteriorated during corticosteroid therapy. to the allele. Because there are 22 alleles of DR4 in the 1995 In contrast, DRB1*0401 and the DRB1*0401-DRB4*0103 nomenclature report, the DR4 alleles can range from haplotype were associated with a lower frequency of DRB1*0401 to DRB1*0422. 11 death from liver failure or the need for transplantation Recent studies have indicated that DRB1*0301 is the printhan patients with other alleles (0% vs. 37%, P Å .03). cipal risk factor in white patients of northern European exPatients with DRB1*0301 differed from those with traction, that DRB1*0401 has a lesser degree of association, DRB1*0401 in that they were younger and failed treat-and that these two DRB1 alleles are independent markers of ment more commonly (27% vs. 5%, P Å .04). We conclude disease susceptibility. 3,7,12,13 Furthermore, the reported assothat alleles associated with susceptibility to type 1 auto-ciations with DRB3*0101 and DRB4*0103 may arise through immune hepatitis also influence its clinical ...

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.

In the search for factors which may influence susceptibility to and outcome from chronic hepatitis C virus (HCV) infection, few studies have considered the influence of host genes. In the present investigation we have performed HLA DRB1, DQA1, DQB1, and DPB1 genotyping on 104 northern European patients with chronic HCV infection and 177 racially and geographically matched controls. Three HLA class II alleles, DRB1*0403, DQA1*03, and DQB1*0302 were present at a significantly lower frequency in patients compared with controls (4.9% vs. 13%, 20.7% vs. 41.2%, and 11.4% vs. 30.5%, respectively) though only two DQB1*0302 and DQA1*03 were significant after correction for multiple testing (pc = 0.038, and pc = 0.046, respectively). No further HLA associations with chronic HCV infection were observed and there was no correlation between stage of disease and HLA genotype. These data provide the first suggestion that susceptibility to chronic HCV infection may be influenced by the hosts' HLA DQ alleles.

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