Pediatric and adult forms of type I autoimmune hepatitis in Argentina: Evidence for differential genetic predisposition

The aim of this study was to compare major histocompatibility complex (MHC) class II susceptibility to type 1 autoimmune hepatitis (AH) between childr en and adults of the same ethnic group. HLA-DRB1, HLA-DRB3, HLA-DQA1, and H LA-DQB1 gene subtypes were examined by high resolution oligonucleotide typi ng in 122 pediatric (PAH) and 84 adult (AAH) patients and in 208 controls, In children, HLA-DRB1*1301 was the primary susceptibility allele (66.4% pat ients vs. 10.6% controls, relative risk [RR] = 16.3, Pc < 10(-24)) whereas HLA-DRB1*1302, which differs from HLA-DRB1*1301 by only 1 amino acid, appea red to be protective. The exclusion of individuals with HLA-DRB1*1301 from control and pediatric patients allowed us to find a secondary association o f PAH with HLA-DRB1*0301. Possession of HLA-DRB1*1301, however, was associa ted with a lower therapeutic response rate. Analysis of peptide binding poc ket residues indicated that Tyr 10, Ser 11, Ser 13, and Val 86 in the class II beta chain were present in 85% of patients compared with 37% of control s, suggesting that a high proportion of AH susceptibility is attributable t o these residues (etiologic fraction [EF] = 76%). In contrast to the class TT associations in children, AAH was associated with HLA-DRB1*0405 (RR = 10 .4, Pc < .005) but not with HLA-DRB1*1301 or HLA-DRB1*0301, In addition, HL A-DP4 with the class I gene, HLA-A11, appeared synergistic in predisposing AAH patients to develop extra-hepatic autoimmune (AI) manifestations (odds ratio [OR] = 104.9, Pc < 10(-4)). Concomitant differences in autoantibody p rofiles were also observed in PAH versus AAH: smooth muscle antibodies (SMA ) were most prevalent in PAH but antinuclear antibodies were most prevalent in AAH (P = .003), This study therefore reveals that different HLA-DRB1 al lotypes confer susceptibility to AH in children and adults and raises the p ossibility that PAH and AAH may be triggered by different factors.