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 mo tif, LLEQKR, within the DR beta polypeptide, but these data are in con flict with contemporary reports from Japan and Argentina. The purpose of the present study was to reexamine this question in a large indepen dent cohort of patients, Methods: Eighty-six North American white pati ents 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 DPB10301 (corrected p robability [Pc] = 0.00003; relative risk [RR] = 4.58), and a secondary association with DPB10401 was identified (Pc = 0.000132; RR = 5.97), Protection from disease was associated with the DRB50101-DRB1*1501 h aplotype (Pc = 0.021; RR = 0.3), However, further analysis indicated t hat a lysine residue at position 71 of the DR beta polypeptide may be the most important determinant of disease susceptibility (P = 0.000000 3; RR = 8.6, increasing to RR = 16.38 with four lysine residues). Conc lusions: DRB10302 and DRB1*0401 are confirmed as the principal suscep tibility alleles for type 1 autoimmune hepatitis, and these data suppo rt the hypothesis that a lysine residue at position 71 of the DR beta- polypeptide chain may be the major risk factor.