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][7][8][9][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 comthis 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 Γ
.01). DRB1*0301 (86% vs. numbers of the code represent the old allelic group that often 45%, P Γ
.008) and the DRB1*0301-DRB3*0101 haplotype is equivalent to the serologically defined antigen. Thus, in (79% vs. 42%, P Γ
.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 Γ
.03). cipal risk factor in white patients of northern European ex-Patients 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 treatand that these two DRB1 alleles are independent markers of ment more commonly (27% vs. 5%, P Γ
.04). We conclude disease susceptibility. 3,7,12,13 Furthermore, the reported assothat alleles associated with susceptibility to type 1 autociations with DRB3*0101 and DRB4*0103 may arise through immune hepatitis also influence its clinical features and strong linkage dysequilibrium with the DRB1*0301 and prognosis. DRB4*0103 is associated with concurrent im-DRB1*0401 alleles, respectively. 7,12,13 This latter explanation mune diseases, DRB1*0301 with a poor treatment reis almost certainly true for associations with the HLA A, B, sponse, and DRB1*0401 with a lower frequency of he-DQA, and DQB alleles, which are in weaker, but not insignifipatic death or transplantation. (HEPATOLOGY 1997; cant, linkage dysequilibrium with the DRB1 alleles. 25:317-323.)
Analyses of amino acid sequence variations that are encoded by the putative susceptibility alleles suggest that the presence of a lysine in position 71 of the DRb polypeptide HLA DR3 and HLA DR4 are risk factors for type 1 autoimchain, encoded by both DRB1*0301 and DRB1*0401, is assomune hepatitis in northern Europe and North America. [1][2][3] ciated with an increased risk for type 1 autoimmune hepati-These antigens have also been associated with the variable tis, and that a susceptibility gene may reside in the DRB1 clinical manifestations of the disease and outcomes after corlocus. 13 The alleles DRB1*0301 and DRB3*0101 encode for ticosteroid therapy. [4][5][6][7][8][9][10] The HLA DR3 and/or DR4 alleles are the lysine residue in this position; thus, the DRB1*0301found in 80% to 85% of individuals with the diagnosis. [3][4][5][6][7] Con-DRB3*0101 haplotype carries a double dose of lysine at current extrahepatic immunologic diseases occur less fre-DRb71. In contrast, the DRB1*0401 allele encodes for a lyquently in the DR3-positive patients, 4,6 and these individuals sine residue in this position, whereas DRB4*0103 encodes have more severe disease at presentation than counterparts for an arginine at DRb71. Consequently, the DRB1*0401-DRB4*0103 haplotype encodes for only a single lysine at the critical DRb71 position, and this may account for the weaker association of DRB1*0401 with disease susceptibility. 12,13 Abbreviations: SMA, smooth muscle antibodies; ANA, antinuclear antibodies. From the 1 Division of Gastroenterology and Internal Medicine, and the 2 Department of The lysine residue is a large, branched molecule that is