2-LOCUS INVOLVEMENT IN THE ASSOCIATION OF HUMAN-LEUKOCYTE ANTIGEN WITH THE EXTRAHEPATIC MANIFESTATIONS OF AUTOIMMUNE CHRONIC ACTIVE HEPATITIS

We investigated the association of human leukocyte antigen antigens an d type I chronic active ''autoimmune'' hepatitis in a population of 65 white Argentinian patients, taking into account the different manifes tations of the disease. Standard microlymphocytotoxicity was used for human leukocyte antigen A, B, C, DR and DQ typing. Human leukocyte ant igen class 2 alleles were also typed on genomic DNA by means of polyme rase chain reaction amplification and hybridization to sequence specif ic oligonucleotides. A primary association with human leukocyte antige n DR4 was present (human leukocyte antigen DR4: 44% in patients vs. 29 % in controls; chi(2), 5.6; p = 0.02, relative risk, 2.1). However, a novel association was observed with human leukocyte antigen All (31% i n patients vs. 6% in the controls; chi(2), 25.3; corrected p = 0.001; relative risk, 6.8). Moreover, of the 20 human leukocyte antigen All p atients, 18 had extrahepatic manifestations associated with autoimmune chronic active hepatitis. This represented 60% of the patients bearin g this form of the disease (n = 30), conferring a relative risk of 22. 2 (chi(2), 46.3; corrected p = 0.00008). In this group, human leukocyt e antigen DR3 and DR4 had a weak association. When present together, h uman leukocyte antigen DR4 and human leukocyte antigen All had a syner gistic effect, yielding an odds ratio of 357. Statistical analysis and family segregation studies suggest that the two loci products may rep resent independent risk factors for this form of autoimmune chronic ac tive hepatitis. This synergistic effect was not evident with All plus DR3. In autoimmune chronic active hepatitis patients without extrahepa tic manifestations, a weak association with human leukocyte antigen DR 6 was found. Interestingly, in autoimmune chronic active hepatitis of childhood (in which extrahepatic manifestations are seldom observed) a strong association with human leukocyte antigen DR6 was recently obse rved in patients from the same ethnic group and geographic region. The clinical and genetic heterogeneity observed in this study may explain the weak human leukocyte antigen associations reported previously for autoimmune chronic active hepatitis and suggest that the extrahepatic forms in patients with autoimmune chronic active hepatitis represents a separate clinical entity.