Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus.
Susceptibility to autoimmune hepatitis type I (AIH-1) has been associated with HLA-DR3, DR52, and DR4 antigens in Caucasian and Oriental patients. However, in Brazil, disease susceptibility is primarily linked to DR13 and DR52. In this highly admixed population, we find different DR13-associated haplotypes, presenting a unique opportunity to discriminate relevant genes within a tightly linked genomic region. To identify the primary susceptibility locus, we sequenced DR13 alleles of 39 patients with AIH-1 and 22 controls. Patients were almost exclusively DRB1*1301, but half of controls typed DRB1*1302. HLA-DQ haplotypes were varied. Oligotyping of DRB3 locus of all patients and also within the HLA-DR13 positive group showed an allele distribution comparable to controls, confirming that the stronger association lies in the DRB1 locus. On the other hand, if DRB1*1301 is the major susceptibility factor in our sample, the only amino acid different from DRB1*1302 in position 86, corresponding to pocket 1 in the peptide-presenting groove, may be important. We propose that peptide presentation leading to pathogenesis of AIH-1 may be quite stringent, but will also be affected by other strong genetic or environmental susceptibility factors, which would explain the various HLA molecules associated to the disease in the different populations.
Goldberg
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AC
Heart Institute, Faculty of Medicine, São Paulo University, Brazil. goldberg@usp.br
Bittencourt
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PL
Mougin
B
B
Cançado
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EL
Porta
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G
Carrilho
F
F
Kalil
J
J
D000483:Alleles; D020816:Amino Acid Motifs / Q000235:genetics; D005819:Genetic Markers / Q000276:immunology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D006239:Haplotypes / Q000276:immunology*; D019693:Hepatitis, Autoimmune / Q000145:classification / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans
D005819:Genetic Markers; D006680:HLA Antigens; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains